Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli. The TGI was studied in a group of 78 female and 58 male undergraduate students and was evoked by placing the palm of the right hand on the thermal grill (20/40 °C interleaved stimulus). Sex-related thermal perception was investigated by a retrospective analysis of thermal detection and thermal pain threshold data that had been measured in student laboratory courses over 5 years (776 female and 476 male undergraduate students) using the method of quantitative sensory testing (QST). To analyse correlations between thermal pain sensitivity and the TGI, thermal pain threshold and the TGI were determined in a group of 20 female and 20 male undergraduate students. The TGI was more pronounced in females than males. Females were more sensitive with respect to thermal detection and thermal pain thresholds. Independent of sex, thermal detection thresholds were dependent on the baseline temperature with a specific progression of an optimum curve for cold detection threshold versus baseline temperature. The distribution of cold pain thresholds was multi-modal and sex-dependent. The more pronounced TGI in females correlated with higher cold sensitivity and cold pain sensitivity in females than in males. Our finding that thermal detection threshold not only differs between the sexes but is also dependent on the baseline temperature reveals a complex processing of “cold” and “warm” inputs in thermal perception. The results of the TGI Background Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli. This allows further investigation of thermal sensation circuitries as earlier studies have analysed thermal detection thresholds only at baseline temperatures around the neutral/comfort zone of 32 °C [ 24 , 25 ]. After finding sex differences in TGI and QST data, the objective was to test the hypothesis of a sex-dependent correlation of the TGI with the subject’s thermal sensitivity and/or thermal pain sensitivity. Therefore, we correlated the TGI with cold or warm sensation and, in addition, with thermal pain sensitivity. Sex differences in thermal thresholds To investigate sex differences in thermal detection and thermal pain threshold, a total of 9940 records from 1252 students (776 females and 476 males) were analysed. Thermal detection thresholds (CDT, WDT) were measured on the ventral surface of the forearm. Mean threshold values (°C from baseline) are shown in Fig. 3 and means ± SEM are summarized in Table 3 . Both CDT and WDT were dependent on the baseline (adaptation) temperature, i.e. the starting temperature of the thermal ramp stimulus. We found that the mean detection threshold of females and males differed by 0.2–0.4 °C, with females reporting higher (less cold) CDT values and lower (less warm) WDT values than males, indicating thermal sensitivity is higher in females than in males (see Table 3 and Fig. 3 ). The sex difference in WDT was more pronounced at low skin temperatures, e.g. 1.5 °C for WDT 20 °C and WDT 25 °C (see Fig. 3b ), a new finding that reveals clear sex differences in warm detection threshold at slightly cool (25 °C) or cold (20 °C) skin temperatures thus implying sex differences in the complex processing of “cold” and “warm” inputs in thermal perception. According to Lötsch and colleagues [ 31 ], the localization of the first and second Gaussians may be interpreted as reflecting the contribution of the TRPM8 receptor that starts to respond at 24 °C [ 32 ] and the TRPA1 receptor that starts to sense cold at 17 °C [ 33 ]. Sex differences were found for these Gaussians in the present study indicating sex-dependent receptor characteristics at the skin area where the cold stimuli had been applied. For the Gaussian with mode at 2 °C, a sex-dependent difference of response probability was found (female 15%, male 32%, respectively (see Additional file 3 : Table S2) indicating that other temperature-sensing receptors, e.g. Studies to date have addressed thermal detection thresholds at baseline temperatures around the neutral/comfort zone, usually 32 °C, which is approximately the mean skin temperature at standard ambient temperature [ 24 , 25 ]. Our data demonstrate that, independent of sex, the CDT as a function of the baseline temperature has the form of an optimum curve with the optimum in the range 25–30 °C. In humans, innocuous skin temperatures of cold are signalled by cold-sensitive Aδ fibres [ 13 , 34 ]. Recently, a micro-neurography study in humans has shown that the response rate of an Aδ fibre to a staircase cold stimulation has the form of an optimum curve with the maximum response rate at 26 °C baseline temperature and lower response rates at lower or higher baseline temperatures (see Fig. 7 in [ 34 ]. Hence, our CDT data (see Fig. 3a ) might be explained by Aδ fibre activation. In addition, the activity of C2 fibres, a population of C fibres responding to warming and innocuous cooling [ 34 ] is likely to play a role.