OBJECTIVE: Few studies have investigated the role of dietary factors on knee osteoarthritis (OA) progression. We examined the prospective association of dietary fat intake with radiographic progression of knee OA. METHODS: In the Osteoarthritis Initiative, 2,092 participants with radiographic knee OA and having baseline dietary data were followed at yearly intervals up to 48 months. Dietary intakes of fatty acids were assessed with the Block Brief Food Frequency Questionnaire. To evaluate radiographic progression of knee OA, we used quantitative joint space width (JSW) between the medial femur and tibia of the knee based on fixed-flexion posteroanterior radiographs. Linear mixed models for repeated measures were used to test the association between dietary fat and JSW loss over time. RESULTS: We observed significant positive relationships of total fat and saturated fatty acids (SFA) intakes with JSW loss. With increasing quartiles of total fat intake, JSW decreases over 48 months were 0.26 mm, 0.27 mm, 0.31 mm and 0.35 mm, respectively (P = 0.02 for trend). Similar association was observed between SFA intake and JSW loss. In contrast, higher intakes of mono- (MUFA) and polyunsaturated fatty acids (PUFA), and higher ratio of PUFA to SFA were associated with a reduced JSW loss. CONCLUSION: High intakes of total fat and SFA may be associated with increased structural knee OA progression, while MUFA and PUFA may reduce radiographic progression. Replication of these novel findings in other prospective studies is needed to confirm if reduction in SFA intake and increase in unsaturated fat intake lead to delayed knee OA progression.