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Anatomical knee joint features and osteoarthritis (OA) severity are associated, however confirming causals link to altered knee loading is challenging. This study leverages statistical shape models (SSM) to investigate the relationship between joint shape/alignment and knee loading during gait in knee OA (KOA) patients to understand their contribution to elevated medial knee loading in OA. Musculoskeletal (MSK) models were created for the mean as well as the first eight SSM principal modes of variation (−3,−2,−1, +1, +2, +3 standard deviations for each mode) and used as input to a MSK modeling framework. Using an identical KOA gait pattern (i.e., joint kinematics and ground reaction forces), we ran simulations for each MSK model and evaluated medial compartment loading magnitude and contact distribution at the instant of first and second peak of knee joint loading. An increase in external rotation, posterior tibia translation and a decrease in medial joint space and medial femoral condylar size predisposed the medial compartment knee joint to overloading during gait. This was coupled with an anterior and medial shift in contact location with increasing external rotated tibial position and increasing posterior tibial translation with respect to the femur. Next, results also highlighted a posterior shift of the medial compartment loading location with decreasing medial joint space. This study provides important population‐based insights on how knee shape and alignment predispose individuals with KOA to elevated medial compartmental knee loading. This information can be crucial in assessing the risk for medial KOA development and progression. [ABSTRACT FROM AUTHOR]