Abstract Objective We examined the independent risk of incident comorbidities associated with prescribed oral paracetamol, NSAIDs and opioids and their interaction and mediation with osteoarthritis (OA). Methods Exposure of these analgesics and the association with nine systemic groups of incident comorbidities were examined in this 5-year cohort study of 261,273 people with incident OA and 261,273 age, sex, and practice matched controls (no OA), in the large UK primary care database. A propensity score adjusted time varying exposure analysis was undertaken using multivariable Cox models to estimate the hazard ratios (HR) for incident comorbidities associated with OA and analgesics. Interaction was defined when the combined term for OA and analgesic was significant. The proportion of the risk associated with OA mediated by analgesics was also calculated. Results The mean age of the cohort was 60 years and 57.7% were female. NSAIDs and opioids were independently associated with all comorbidities. Paracetamol interacted with OA leading to an extra risk of renal comorbidities (mHR 1.14, 95%CI 1.06, 1.22). NSAIDs and opioids interacted with OA with extra risk of cardiovascular (mHR 1.05, 95%CI 1.01, 1.11 and mHR 1.06, 95%CI 1.02, 1.11) and endocrine (mHR 1.11, 95%CI 1.05, 1.17 and mHR 1.08, 95%CI 1.02, 1.13) comorbidities, respectively. About 16% and 7% risk from OA to psychological comorbidities were indirectly mediated by NSAIDs and opioids, respectively. Conclusion Our findings suggest that in people with OA, analgesic prescriptions may be associated with increased risk of a certain incident comorbidities, particularly in long-term use.