Trochlear groove geometry and the location of the tibial tubercle, where the patellar tendon inserts, have both been associated with patellofemoral instability and can be modified surgically. Although their effects on patellofemoral biomechanics have been investigated individually, the interaction between the two is unclear. The authors’ aim was to use statistical shape modeling and musculoskeletal simulation to examine the effect of patellofemoral geometry on the relationship between tibial tubercle location and patellofemoral function. A statistical shape model was used to generate new knee geometries with trochlear grooves ranging from shallow to deep. A Monte Carlo approach was used to create 750 knee models by randomly selecting a geometry and randomly translating the tibial tubercle medially/laterally and anteriorly. Each knee model was incorporated into a musculoskeletal model, and an overground walking trial was simulated. Knees with shallow trochlear geometry were more sensitive to tubercle medialization with greater changes in lateral patella position (−3.0 mm/cm medialization shallow vs −0.6 mm/cm deep) and cartilage contact pressure (−0.51 MPa/cm medialization shallow vs 0.04 MPa/cm deep). However, knees with deep trochlear geometry experienced greater increases in medial cartilage contact pressure with medialization. This modeling framework has the potential to aid in surgical decision making.