OBJECTIVE: To examine the relationship of knee osteoarthritis (OA) with cardiovascular and metabolic risk factors by obesity status and gender. METHODS: Data from 1,066 National Health and Nutrition Examination Survey III participants (>/=60 years of age) was used to examine relationships of osteophytes-defined radiographic knee OA and cardiovascular and metabolic measures. Analyses were considered among obese [body mass index (BMI)>/=30 kg/m(2)] and non-obese (BMI<30 kg/m(2)) men and women. RESULTS: The prevalence of osteophytes-defined radiographic knee OA was 34%. Leptin levels and homeostatic model assessment-insulin resistance (HOMA-IR), a proxy measure of insulin resistance, were significantly associated with knee OA; those with knee OA had 35% higher HOMA-IR values and 52% higher leptin levels compared to those without knee OA. The magnitude of the association between HOMA-IR and knee OA was strongest among men, regardless of obesity status; odds ratios (ORs) for HOMA-IR were 34% greater among non-obese men (OR=1.18) vs obese women (OR=0.88). Among obese women, a 5-mug/L higher leptin was associated with nearly 30% higher odds of having knee OA (OR=1.28). Among men, ORs for the association of leptin and knee OA were in the opposite direction. CONCLUSIONS: Cardiometabolic dysfunction is related to osteophytes-defined radiographic knee OA prevalence and persists within subgroups defined by obesity status and gender. A sex dimorphism in the direction and magnitude of cardiometabolic risk factors with respect to knee OA was described including HOMA-IR being associated with OA prevalence among men while leptin levels were most important among women.