Abstract Background Many clinical practice guidelines are based on randomised controlled trials conducted in secondary or tertiary care setting and general practitioners frequently question their relevance for primary care patients. Our aim was to compare the intervention effect estimates between primary care setting randomised controlled trials (PC-RCTs) and secondary or tertiary care setting randomised controlled trials (ST-RCTs). Methods Meta-epidemiological study of meta-analyses (MAs) of a binary outcome including at least one PC-RCT and one ST-RCT. PC-RCTs were defined as trials recruiting patients in general practices, primary care practices, family practices, community centers or community pharmacies. ST-RCTs were defined as trials recruiting in hospitals, including hospitalized patients, hospital outpatients and patients from emergency departments. For each MA, we estimated a ratio of odds ratio (ROR) by using random-effects meta-regression, with an ROR less than 1 indicating lower estimates of the intervention effect in PC-RCTs than ST-RCTs. Finally, we estimated a combined ROR across MAs by using a random-effects meta-analysis. We performed subgroup analyses considering the type of outcomes (objective vs subjective), type of experimental intervention (pharmacological vs non-pharmacological), and control group (active vs inactive) as well as analyses adjusted on items of the Cochrane Risk of Bias tool. Results Among 1765 screened reviews, 76 MAs with 230 PC-RCTs and 384 ST-RCTs were selected. The main medical fields were pneumology (13.2%) and psychiatry or addictology (38.2%). Intervention effect estimates did not significantly differ between PC-RCTs and ST-RCTs (ROR = 0.97, 95% confidence interval 0.88 to 1.08), with moderate heterogeneity across MAs (I 2 = 45%). Subgroup and adjusted analyses led to consistent results. Conclusion We did not observe any significant difference in intervention effect estimates between PC-RCTs and ST-RCTs. Nevertheless, most of the medical fields in this meta-epidemiological study were not representative of the pathologies encountered in primary care. Further studies with pathologies more frequently encountered in primary care are needed.