The purpose of this study was to understand how the form (i.e., shape and presence of underlying soft tissue) of residual limb tissue influences limb function and comfort for individuals with transfemoral limb loss. Specifically, there exist surgical techniques that are frequently applied to the lower limbs of individuals to reduce an excessive soft tissue envelope. However, the clinical goals are frequently from a cosmetic perspective and are applied most commonly to individuals who are obese and not necessarily those with limb loss. For specific individuals with transfemoral limb loss, there likely exist limb shapes and distributions of underlying soft tissue that more optimally engage with lower-limb prostheses. Based on recent experimental findings, optimizing the limb and its physical connection to lower-limb prostheses, may have equivalent if not greater impact on user outcomes than selection of prosthetic components. This study develops and tests a method for informing optimal designs of the residual limb for individuals with transfemoral amputation. The framework uses patient-specific MRI images of an individual's residual limb, and within a mechanical modeling framework applies Latin hypercube sampling to investigate which portions of the underlying limb tissue most positively affect mechanical objectives associated with limb function and comfort. These theoretical results predicted from this system aimed to inform optimal limb designs were then compared to a currently used surgical method known as medial thighplasty, which was previously applied in one patient, to assess agreement. These simulations showed that the regions of the limb most contributing negatively to the objective function were located at the distal end of the limb and were far from muscle tissue (i.e., were mostly superficial). These findings suggest that limb techniques which seek to produce residual limbs that are most slim at their medial and distal end are beneficial and may lead to improved fit and function of lower-limb prostheses.Clinical Relevance-Prosthetic technology advancement within the last decade has heightened the hopes of individuals with amputation. However, how these devices integrate to their human users is non-trivial and can curtail these advancements. Tools are needed to inform how residual limb itself can be optimized to better integrate with prostheses.