© 2018 Osteoarthritis Research Society International Objective: To determine the sex-specific relation of frontal plane alignment (FPA) to magnetic resonance imaging (MRI)-defined features of patellofemoral osteoarthritis, and also to tibiofemoral osteoarthritis and knee pain. Method: The Multicenter Osteoarthritis Study is cohort study comprised of individuals with or at risk of knee osteoarthritis. We determined the sex-specific dose–response relation of baseline FPA to MRI-defined patellofemoral and tibiofemoral structural worsening, and incident knee pain, over 7 years. Results: In women only, greater varus alignment was associated with medial patellofemoral osteophytes (risk ratio [RR] 1.7 [95% CI 1.2, 2.6]) and valgus with lateral patellofemoral osteophytes (RR 1.9 [1.0, 3.6]). In men, greater varus increased risk for medial tibiofemoral cartilage worsening (RR 1.7 [1.1, 2.6]), and valgus for lateral tibiofemoral cartilage worsening (RR 1.8 [1.6, 2.2]). In women, findings were similar for tibiofemoral cartilage, but varus also increased risk for medial bone marrow lesions [BMLs] (RR 2.2 [1.6, 3.1]) and medial osteophytes (RR 1.8 [1.3, 2.5]), and valgus for lateral BMLs (RR 3.3 [2.2, 4.5]) and osteophytes (RR 2.0 [1.2, 3.2]). Varus increased risk of incident pain in men (RR 1.7 [1.4, 2.2]) and women (RR 1.3 [1.0, 1.6]), valgus did so in men only (RR 1.5 [1.1, 1.9]). Conclusion: FPA was associated with patellofemoral osteophyte worsening in women, though overall was more strongly associated with tibiofemoral than patellofemoral osteoarthritis feature worsening. FPA in women was more consistently associated with structural worsening, yet men had higher associations with incident pain.