Thigh muscle weakness is a risk factor for incident radiographic and symptomatic knee osteoarthritis (KOA). The role of thigh muscle weakness in radiographic and/or symptomatic KOA progression remains elusive. Five hundred twenty-seven knees of 527 Osteoarthritis Initiative participants with baseline Kellgren-Lawrence grades 1 to 3 were included in this nested case-control study evaluating whether baseline muscle strength predicted symptomatic and/or radiographic KOA progression. Case knees (n = 173) displayed both medial tibiofemoral joint space loss (≥0.7 mm) and a persistent increase in Western Ontario McMasters Osteoarthritis Index pain (≥9 on a 0- to 100-point scale) over 24 to 48 months from baseline. Control knees (n = 354) included 174 with neither radiographic nor symptomatic progression, 91 with radiographic progression only, and 89 with symptomatic progression only. Isometric knee extensor and flexor strength were recorded at baseline. Using logistic regression models, muscle strength was not associated with case status. However, knee extensor (odds ratio, 1.7; 95% confidence interval, 1.1-3.3; P = 0.035) and flexor weakness (odds ratio, 2.0; 95% confidence interval, 1.1, 3.3; P = 0.016) predicted isolated symptomatic progression in males, but not in females. The results indicate that thigh muscle strength may affect symptomatic and structural progression differently in males with KOA and identify an important window for potentially lowering risk of symptomatic osteoarthritis progression in men.