Femoral anterior cruciate ligament (ACL) graft malposition may lead to clinical instability and graft failure. The purpose of this study was to evaluate the effect of ACL graft placement on global knee biomechanics using finite element (FE) analysis. An established nonlinear contact FE model was used to evaluate 25 distinct tunnel loci representing primary ACL reconstructions; knee flexion and a simulated Lachman maneuver was used to assess knee joint laxity, meniscal stress, in situ graft loading, and peak articular cartilage contact pressure for each of the tunnel positions. Increased anterior tibial translation during Lachman testing was observed when the femoral graft was moved from anterior, anterior/inferior, and posterior/inferior relative to the anatomic footprint. Cartilage contact pressure and meniscal stresses increased with anterior graft placement. Peak stresses in the ACL grafts increased with significant posterior and inferior placement (5-7.5 mm) from the anatomic location. Global joint biomechanics are lease favorable with anterior graft placement. Excessive posterior/inferior placement (> 5 mm) may subject grafts to increased pressures.