OBJECTIVE: Use of specific medications may accelerate the progression of radiographic knee osteoarthritis (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA. METHODS: We used longitudinal data from the Osteoarthritis Initiative (OAI); an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (KL grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96-months follow-up. We used random-effects, panel-regression to assess the association between current medication use (non-users as reference group) and change in mJSW. RESULTS: Of 2,054 eligible participants, 2,003 participants with baseline mJSW data were included (55.7% female, mean age 63.3 (SD 8.98) years). Of 7 medication classes, at baseline non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use were frequent and, the following comorbidity medications were used most frequently; i) statins (27.4%), ii) anti-hypertensives (up to 15.0%), iii) anti-depressant/anxiolytics/psychotropics (14.0%), iv) osteoporosis-related medication (10.9%) and v) diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = -0.042, 95% CI -0.08 to -0.0004). No other associations were observed. CONCLUSIONS: In current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.