Running-specific prostheses (RSF) are designed to replicate the spring-like nature of biological legs (bioL) during running. However, it is not clear how these devices affect whole leg stiffness characteristics or running dynamics over a range of speeds. We used a simple spring-mass model to examine running mechanics across a range of speeds, in unilateral and bilateral transtibial amputees and performance-matched controls. We found significant differences between the affected leg (AL) of unilateral amputees and both ALs of bilateral amputees compared with the bioL of non-amputees for nearly every variable measured. Leg stiffness remained constant or increased with speed in bioL, but decreased with speed in legs with RSPs. The decrease in leg stiffness in legs with RSPs was mainly owing to a combination of lower peak ground reaction forces and increased leg compression with increasing speeds. Leg stiffness is an important parameter affecting contact time and the force exerted on the ground. It is likely that the fixed stiffness of the prosthesis coupled with differences in the limb posture required to run with the prosthesis limits the ability to modulate whole leg stiffness and the ability to apply high vertical ground reaction forces during sprinting.