Medial opening wedge high tibial osteotomy (MOWHTO) is a surgical procedure to treat knee osteoarthritis associated with varus deformity. However, the ideal final alignment of the Hip-Knee-Ankle (HKA) angle in the frontal plane, that maximizes procedural success and post-operative knee function, remains controversial. Therefore, the purpose of this study was to introduce a subject-specific modeling procedure in determining the biomechanical effects of MOWHTO alignment on tibiofemoral cartilage stress distribution. A 3D finite element knee model derived from magnetic resonance imaging of a healthy participant was manipulated in-silico to simulate a range of final HKA angles (i.e. 0.2 degrees, 2.7 degrees, 3.9 degrees and 6.6 degrees valgus). Loading and boundary conditions were assigned based on subject-specific kinematic and kinetic data from gait analysis. Multiobjective optimization was used to identify the final alignment that balanced compressive and shear forces between medial and lateral knee compartments. Peak stresses decreased in the medial and increased in the lateral compartment as the HKA was shifted into valgus, with balanced loading occurring at angles of 4.3 degrees and 2.9 degrees valgus for the femoral and tibial cartilage respectively. The concept introduced here provides a platform for non-invasive, patient-specific preoperative planning of the osteotomy for medial compartment knee osteoarthritis. (C) 2017 IPEM. Published by Elsevier Ltd. All rights reserved.