Subjects with amputation of the lower limbs are at increased risk of cardiovascular mortality and morbidity. We hypothesize that amputation-induced alterations in the arterial tree negatively impact arterial biomechanics, blood pressure and flow behavior. These changes may interact with other biological factors, potentially increasing cardiovascular risk. To evaluate this hypothesis regarding the purely mechanical impact of amputation on the arterial tree, we used a simulation computer model including a detailed one-dimensional (1D) arterial network model (143 arterial segments) coupled with a zero-dimensional (0D) model of the left ventricle. Our simulations included five settings of the arterial network: (1) 4-limbs control, (2) unilateral amputee (right lower limb), (3) bilateral amputee (both lower limbs), (4) trilateral amputee (lower-limbs and right upper-limb), and (5) quadrilateral amputee (lower and upper limbs). Analysis of regional stiffness, as calculated by pulse wave velocity (PWV) for large-, medium- and small-sized arteries, showed that, while aortic stiffness did not change with increasing degree of amputation, stiffness of medium and smaller-sized arteries increased with greater amputation severity. Despite a staged decrease in cardiac output, the systolic and diastolic blood pressure values increased, resulting in an increase in both central and peripheral pulse pressures but with an attenuation of pulse pressure amplification. The most significant increase in peak systolic pressure and decrease in peak systolic blood flow was observed at the site of the abdominal aorta. Wave separation analysis indicated no changes in the shape of the forward and backward wave components. However, the results from wave intensity analysis showed that with extended amputation, there was an increase in peak forward wave intensity and a rise in the inverse peak of the backward wave intensity, suggesting potential alterations in cardiac hemodynamic load. In conclusion, this simulation study showed that biomechanical and hemodynamic changes in the arterial network geometry could interact with additional risk factors to increase the cardiovascular risk in patients with amputations.