OBJECTIVE: The purpose of this study was to estimate the effectiveness of the combination of glucosamine and chondroitin in relieving knee symptoms and slowing disease progression among patients with knee osteoarthritis (OA). METHODS: The 4-year followup data from the Osteoarthritis Initiative data set were analyzed. We used a "new-user" design, for which only participants who were not using glucosamine/chondroitin at baseline were included in the analyses (n = 1,625). Cumulative exposure was calculated as the number of visits when participants reported use of glucosamine/chondroitin. Knee symptoms were measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and structural progression was determined by measuring the joint space width (JSW). To control for the time-varying confounders that might be influenced by previous treatments, we used marginal structural models to estimate the effects on OA of using glucosamine/chondroitin for 3 years, 2 years, and 1 year. RESULTS: During the study period, 18% of the participants initiated treatment with glucosamine/chondroitin. After adjustment for potential confounders with marginal structural models, we found no clinically significant differences between users at all assessments and never-users of glucosamine/chondroitin in WOMAC pain (β = 0.68 [95% confidence interval (95% CI) -0.16 to 1.53]), WOMAC stiffness (β = 0.41 [95% CI 0 to 0.82]), and WOMAC function (β = 1.28 [95% CI -1.23 to 3.79]) or JSW (β = 0.11 [95% CI -0.21 to 0.44]). CONCLUSION: Use of glucosamine/chondroitin did not appear to relieve symptoms or modify disease progression among patients with radiographically confirmed OA. Our findings are consistent with the results of meta-analyses of clinical trials and extend those results to a more general population with knee OA.