CONTEXT AND OBJECTIVE: We evaluated the predictive value of serum cartilage oligomeric matrix protein (sCOMP) levels over 20 years on the development of radiographic (RKOA) and painful knee osteoarthritis (KOA) in a longitudinal cohort of middle-aged women. MATERIALS AND METHODS: Five hundred and ninety-three women with no baseline KOA underwent 5-year knee radiographs over 20-years and were asked about knee pain a month before each assessment. A repeated measures logistic regression model was used where the outcomes were recorded at 5, 10, 15 and 20-years follow-up. RESULTS: The highest quartile of sCOMP was associated with increased risk of RKOA with overall OR of 1.97 (95% CI: 1.33-2.91) over 20 years when compared with the lowest sCOMP quartile. The association with painful KOA was similar and also independent, but only when the fourth and third sCOMP quartiles were compared. DISCUSSION AND CONCLUSION: This study demonstrates that sCOMP levels are predictive of subsequent structural changes and incidence of painful KOA, independently of age and BMI.