© 2018, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: Reports on quadriceps weakness as a risk factor for incident and progressive knee osteoarthritis are conflicting, potentially due to differing effects of muscle strength on patellofemoral and tibiofemoral compartments. This study aimed to examine the sex-specific relation of quadriceps strength to worsening patellofemoral and tibiofemoral cartilage damage over 84 months. Methods: The Multicenter Osteoarthritis Study is a cohort study of individuals with or at risk for knee osteoarthritis. Maximal quadriceps strength was assessed at baseline. Cartilage damage was semiquantitatively assessed by magnetic resonance imaging at baseline and 84-month follow-up using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Worsening patellofemoral and tibiofemoral cartilage damage was defined as any WORMS score increase in each subregion within medial and lateral compartments separately. Logistic regression with generalized estimating equations was used to assess the sex-specific relation of quadriceps strength to worsening cartilage damage. Results: A total of 1,018 participants (mean ± SD age 61 ± 8 years, and mean ± SD body mass index 29.3 ± 4.5 kg/m2; 64% female) were included. Quadriceps weakness increased the risk of worsening lateral patellofemoral cartilage damage in women (risk ratio for lowest versus highest quartile of strength 1.50 [95% confidence interval 1.03–2.20]; P = 0.007 for linear trend) but not in men. There was generally no association between quadriceps weakness and worsening cartilage damage in the medial or lateral tibiofemoral compartment for either women or men. Conclusion: Low quadriceps strength increased the risk of worsening cartilage damage in the lateral patellofemoral joint of women, suggesting that optimizing quadriceps strength may help prevent worsening of structural damage in the patellofemoral joint in women.