Objective. To examine whether obesity increases the risk of progression of knee osteoarthritis (OA). Methods. We used data from the Multicenter Osteoarthritis Study, a longitudinal study of persons with or at high risk of knee OA. OA was characterized at baseline and 30 months using posteroanterior fixed-flexion radiographs and Kellgren/ Lawrence (K/L) grading, with alignment assessed on full-extremity films. In knees with OA at baseline (K/L grade 2 or 3), progression was defined as tibiofemoral joint space narrowing on the 30-month radiograph. In knees without OA at baseline (K/L grade 0 or 1), incident OA was defined as the development of radiographic OA at 30 months. Body mass index (BMI) at baseline was classified as normal (<25 kg/m 2), overweight (25-<30 kg/m 2), obese (30-<35 kg/m 2), and very obese (≥35 kg/m 2). The risk of progression was tested in all knees and in subgroups categorized according to alignment. Analyses were adjusted for age, sex, knee injury, and bone density. Results. Among the 2,623 subjects (5,159 knees), 60% were women, and the mean ± SD age was 62.4 ± 8.0 years. More than 80% of subjects were overweight or obese. At baseline, 36.4% of knees had tibiofemoral OA, and of those, only one-third were neutrally aligned. Compared with subjects with a normal BMI, those who were obese or very obese were at an increased risk of incident OA (relative risk 2.4 and 3.2, respectively [P for trend < 0.001]); this risk extended to knees from all alignment groups. Among knees with OA at baseline, there was no overall association between a high BMI and the risk of OA progression; however, an increased risk of progression was observed among knees with neutral but not varus alignment. The effect of obesity was intermediate in those with valgus alignment. Conclusion. Although obesity was a risk factor for incident knee OA, we observed no overall relationship between obesity and the progression of knee OA. Obesity was not associated with OA progression in knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment. Therefore, weight loss may not be effective in preventing progression of structural damage in OA knees with varus alignment. © 2009, American College of Rheumatology.