Abstract Background In Belgium, the debate about the effect of the national academic detailing service (ADS) on prescribing quality in general practice is ongoing. In order to evaluate both the implementation strategies of the ADS and its effectiveness on appropriate prescribing of pain relief medication, we conducted a real-world cluster randomized controlled trial (cRCT). Methods In a pragmatic cRCT, all Belgian general practices previously visited by Farmaka were assessed for eligibility and randomized. Only practices randomized to the intervention group were invited for an academic detailing visit on appropriate prescribing of pain relief medication. GPs were unaware of the study, ensuring the production of real-world evidence but were given the option to opt out from the analysis. An objective outcome assessment was obtained using routinely collected reimbursement data. Primary outcomes were the proportion of patients reimbursed for an analgesic or NSAID, the defined daily dose of paracetamol per patient per month, the proportion of patients reimbursed for a recommended NSAID among those reimbursed for any NSAID and the proportion of patients reimbursed for both an NSAID and a proton pump inhibitor among those reimbursed for an NSAID. The impact of practice, GP and academic detailer characteristics were also assessed. Results Three thousand five hundred twenty-nine general practices (4530 GPs) were eligible and randomized. One thousand six hundred ninety-eight practices (2171 GPs) in the intervention group and one thousand seven hundred three (2163 GPs) in the control group were included in the analysis. The intervention had a significant impact on the proportion of patients reimbursed for a recommended NSAID among those reimbursed for any NSAID (increase in odds (95% CI): 19% (10–29%)). A clear impact on other outcomes could not be detected. Additionally, we showed that the characteristics of the academic detailers might impact the effectiveness of the visit. Conclusions National implementation of academic ...