The study objective was to investigate the influence of coronal plane alignment and ligament properties on total knee replacement (TKR) contact loads during walking. We created a subject-specific knee model of an 83-year-old male who had an instrumented TKR. The knee model was incorporated into a lower extremity musculoskeletal model and included deformable contact, ligamentous structures, and six degrees-of-freedom (DOF) tibiofemoral and patellofemoral joints. A novel numerical optimization technique was used to simultaneously predict muscle forces, secondary knee kinematics, ligament forces, and joint contact pressures from standard gait analysis data collected on the subject. The nominal knee model predictions of medial, lateral, and total contact forces during gait agreed well with TKR measures, with root-mean-square (rms) errors of 0.23, 0.22, and 0.33 body weight (BW), respectively. Coronal plane component alignment did not affect total knee contact loads, but did alter the medial–lateral load distribution, with 4 deg varus and 4 deg valgus rotations in component alignment inducing +17% and −23% changes in the first peak medial tibiofemoral contact forces, respectively. A Monte Carlo analysis showed that uncertainties in ligament stiffness and reference strains induce ±0.2 BW uncertainty in tibiofemoral force estimates over the gait cycle. Ligament properties had substantial influence on the TKR load distributions, with the medial collateral ligament and iliotibial band (ITB) properties having the largest effects on medial and lateral compartment loading, respectively. The computational framework provides a viable approach for virtually designing TKR components, considering parametric uncertainty and predicting the effects of joint alignment and soft tissue balancing procedures on TKR function during movement.