Transfemoral prosthesis users typically perform the sit-to-stand motion unilaterally, placing minimal load on the prosthetic side. This increases the risk of injury and accelerates the degeneration of the intact limb. To address this, understanding compensation strategies is essential. Predictive neuromusculoskeletal modeling offers a method to investigate this. The aim of this study was to develop and validate a neuromusculoskeletal model with reflex-based muscle control to simulate the sit-tostand motion in non-amputees and transfemoral amputees with a passive prosthesis. We developed a three-dimensional sit-tostand musculoskeletal model of a non-amputee (20 degrees of freedom, 24 muscles) and a transfemoral amputee (20 degrees of freedom, 19 muscles), both incorporating a two-phase stand-up controller based on an existing two-dimensional reflex controller. We compared the simulation framework to measured kinematics, muscle activations, ground reaction forces, and existing literature on degrees of asymmetry and muscle forces. The developed framework was used to optimize prosthetic knee and ankle stiffness and damping for the sit-to-stand motion with a passive prosthesis. The simulated kinematics of the non-amputee matched measured kinematics. The prosthesis model indicated compensation strategies involving increased thoracic and lumbar extension, lumbar bending towards the non-amputated side,
increased pelvic tilt combined with decreased hip flexion, and heightened muscle activation and force. Optimization results suggested a knee stiffness of 0.1432 [Nm/deg] and damping of 0.0246 [Nm·s/deg], while the ankle required a stiffness of 0.1968 [Nm/deg] and damping of 0.1350 [Nm·s/deg]. These values are recommended for testing in future experiments.