OBJECTIVE: In the perspective of personalized management of osteoarthritis (OA), a clinically relevant concern is the impact of meniscal extrusion (Ext) on response to treatment. This study aimed at determining the effects of conventional OA pharmacological treatments and those of the combination of glucosamine and chondroitin sulfate (Glu/CS) on knee structural changes in the presence or absence of Ext, using data from the progression cohort of the Osteoarthritis Initiative. METHODS: In this longitudinal study, knee OA participants were stratified based on whether (+) or not (-) they received analgesics/NSAIDs (+ and -analgesics/NSAIDs) and/or Glu/CS (+ and -Glu/CS) for 24 consecutive months and on the presence (Ext+) or absence (Ext-) of medial meniscal extrusion at baseline. The main outcomes were knee structural changes including the loss of joint space width (JSW) and cartilage volume loss measured by quantitative MRI. RESULTS: In both - and +analgesics/NSAIDs groups (n = 300 each), the Ext+ participants had more-advanced disease at baseline (T0) and more JSW loss and cartilage volume loss in the medial compartment (p ≤ 0.003, univariate; p ≤ 0.049, multivariate analyses) at both 12 (T12) and 24 (T24) months compared to Ext- participants. In the -analgesics/NSAIDs group, Ext+ participants taking Glu/CS had significantly less cartilage volume loss in the medial plateau at T24 (p ≤ 0.010, univariate and multivariate analyses). In the +analgesics/NSAIDs group at T24, Ext- participants taking Glu/CS had less cartilage volume loss in the global (p ≤ 0.002, univariate and multivariate analyses) and medial and lateral plateaus (p = 0.034 and p = 0.013, respectively, multivariate analysis). No significant difference in JSW loss was found between the groups. CONCLUSION: This study is the first to demonstrate, using qMRI, that meniscal extrusion can modify the response to Glu/CS treatment in knee OA patients, depending on the severity of the disease.