Objective: To compare the effects of neuromuscular exercise (NEXA) and quadriceps strengthening (QS) on the knee adduction moment (an indicator of medio-lateral distribution of knee load), pain and physical function in people with medial knee joint osteoarthritis (OA) and varus malalignment. Methods: 100 people with medial knee pain, mostly moderate to severe radiographic medial knee OA, and varus malalignment were randomly allocated to one of two 12-week exercise programs. Each program involved 14 individually supervised exercise sessions with a physiotherapist plus a home exercise component. Primary outcomes were peak external knee adduction moment (3D gait analysis), pain (visual analogue scale), and self-reported physical function (Western Ontario and McMaster Universities Osteoarthritis Index). Results: 82 participants (38/50 (76%) NEXA, 44/50 (88%) QS) completed the trial. There was no significant between-group difference in the change in the peak knee adduction moment (mean difference (95% CI) 0.134 (-0.069 to 0.337) Nm/(BW.HT)%), pain (2.4 (-6.0 to 10.8) mm) or physical function (-0.8 (-4.0 to 2.4) units). Neither group showed a change in knee moments following exercise, whereas both groups showed similar significant reductions in pain and physical dysfunction. Conclusions: Although comparable improvements in clinical outcomes were found for both neuromuscular and quadriceps strengthening exercise in people with moderate varus malalignment and mostly moderate to severe medial knee OA, these forms of exercise did not affect the knee adduction moment, a key predictor of structural disease progression. Australia and New Zealand Clinical Trials Registry (#ACTRN12610000660088) © 2013 American College of Rheumatology.