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To test the influence of combined knee valgus and internal tibial rotation moment on anterior cruciate ligament (ACL) strain during single-leg landing. We tested the following hypotheses: the combination of the valgus and internal rotation moments observed during single-leg landing produces a higher ACL strain than either moment applied individually, the combined rotational moments at the physiological levels observed could theoretically increase strain in the ACL high enough to rupture the ACL, and the location of the peak contact force was at the posterior-lateral side for combined loading.The study was conducted by applying in vivo human loading data to a validated simulation model of the three-dimensional dynamic knee joint to predict ACL strains.The peak ACL strain increased nonlinearly when either applied valgus moment or internal rotation moment was increased in the model. When the two rotational moments were applied individually, neither caused ACL strain >0.077. However, when applied in combination, the two rotational moments had a much larger effect, and the predicted peak ACL strain increased up to 0.105. During landing, the peak contact force occurred at the posterior-lateral side of the tibial cartilage in the model when the combined maximum valgus moment and tibial internal rotation moments were applied.Combined knee valgus and internal rotation moments increases ACL strain more than either alone. The combination of a valgus and internal rotational moment at magnitudes that occurs in vivo during landing can cause ACL strains that may be high enough to cause ACL rupture. This predicted high ACL strain and the contact force location suggest that combined valgus and internal tibial rotational moments during single-leg landing are relevant to ACL injuries.