Fitting of a prosthetic socket is a critical stage in the process of rehabilitation of a trans-tibial amputation (TTA) patient, since a misfit may cause pressure ulcers or a deep tissue injury (DTI: necrosis of the muscle flap under intact skin) in the residual limb. To date, prosthetic fitting typically depends on the subjective skills of the prosthetist, and is not supported by biomedical instrumentation that allows evaluation of the quality of fitting. Specifically, no technology is presently available to provide real-time continuous information on the internal distribution of mechanical stresses in the residual limb during fitting of the prosthesis, or while using it and this severely limits patient evaluations. In this study, a simplified yet clinically oriented patient-specific finite element (FE) model of the residual limb was developed for real-time stress analysis. For this purpose we employed a custom-made FE code that continuously calculates internal stresses in the residual limb, based on boundary conditions acquired in real-time from force sensors, located at the limb-prosthesis interface. Validation of the modeling system was accomplished by means of a synthetic phantom of the residual limb, which allowed simultaneous measurements of interface pressures and internal stresses. Human studies were conducted subsequently in five TTA patients. The dimensions of bones and soft tissues were obtained from X-rays of the residual limb of each patient. An indentation test was performed in order to obtain the effective elastic modulus of the soft tissues of the residual limb. Seven force sensors were placed between the residual limb and the prosthetic liner, and subjects walked on a treadmill during analysis. Generally, stresses under the shinbones were approximately threefold higher than stresses at the soft tissues behind the bones. Usage of a thigh corset decreased the stresses in the residual limb during gait by approximately 80%. Also, the stresses calculated during the trial of a subject who complained about pain and discomfort were the highest, confirming that his socket was not adequately fitted. We conclude that real-time patient-specific FE analysis of internal stresses in deep soft tissues of the residual limb in TTA patients is feasible. This method is promising for improving the fitting of prostheses in the clinical setting and for protecting the residual limb from pressure ulcers and DTI.