Segment-based musculoskeletal models allow the prediction of muscle, ligament, and joint forces without making assumptions regarding joint degrees-of-freedom (DOF). The dataset published for the “Grand Challenge Competition to Predict in vivo Knee Loads” provides directly measured tibiofemoral contact forces for activities of daily living (ADL). For the Sixth Grand Challenge Competition to Predict in vivo Knee Loads, blinded results for “smooth” and “bouncy” gait trials were predicted using a customized patient-specific musculoskeletal model. For an unblinded comparison, the following modifications were made to improve the predictions: further customizations, including modifications to the knee center of rotation; reductions to the maximum allowable muscle forces to represent known loss of strength in knee arthroplasty patients; and a kinematic constraint to the hip joint to address the sensitivity of the segment-based approach to motion tracking artifact. For validation, the improved model was applied to normal gait, squat, and sit-to-stand for three subjects. Comparisons of the predictions with measured contact forces showed that segment-based musculoskeletal models using patient-specific input data can estimate tibiofemoral contact forces with root mean square errors (RMSEs) of 0.48–0.65 times body weight (BW) for normal gait trials. Comparisons between measured and predicted tibiofemoral contact forces yielded an average coefficient of determination of 0.81 and RMSEs of 0.46–1.01 times BW for squatting and 0.70–0.99 times BW for sit-to-stand tasks. This is comparable to the best validations in the literature using alternative models.