OBJECTIVE: To assess the role of obesity and metabolic dysfunctionality with knee osteoarthritis (OA), knee joint pain, and physical functioning performance, adjusted for joint space width (JSW) asymmetry. METHODS: Knee OA was defined as a Kellgren/Lawrence score > or =2 on weight-bearing radiographs. Obesity was defined as a body mass index > or =30 kg/m2. Cardiometabolic clustering classification was based on having > or =2 of the following factors: low levels of high-density lipoprotein cholesterol; elevated levels of low-density lipoprotein cholesterol, triglycerides, blood pressure, C-reactive protein, waist:hip ratio, or glucose; or diabetes mellitus. The difference between lateral and medial knee JSW was used to determine joint space asymmetry. RESULTS: In a sample of women (n = 482, mean age 47 years), prevalences of knee OA and persistent knee pain were 11% and 30%, respectively. The knee OA prevalence in nonobese women without cardiometabolic clustering was 4.7%, compared with 12.8% in obese women without cardiometabolic clustering and 23.2% in obese women with cardiometabolic clustering. Nonobese women without cardiometabolic clustering were less likely to perceive themselves as limited compared with women in all other obesity/cardiometabolic groups (P < 0.05). Similar associations were seen with knee pain and physical functioning measures. The inclusion of a joint space asymmetry measure was associated with knee OA but not with knee pain or physical functioning. CONCLUSION: Knee OA was twice as frequent in obese women with cardiometabolic clustering compared with those without, even when considering age and joint asymmetry. Obesity/cardiometabolic clustering was also associated with persistent knee pain and impaired physical functioning.