OBJECTIVE: To evaluate the effect of a multifaceted educational intervention on the frequency of antipsychotic co-prescribing in adult schizophrenia out-patients. METHOD: Controlled quasi-experimental study performed in two Danish municipalities matched for baseline prevalence of antipsychotic polypharmacy, socioeconomic status and functional level of patients. The intervention was aimed at psychiatric healthcare providers and consisted of 1 day of didactic lectures, six 3-h educational outreach visits and an electronic reminder during drug prescribing. RESULTS: Between-group use of antipsychotic polypharmacy was compared at baseline (intervention group, N = 232/control group, N = 351) and after 1 year of intervention (intervention group, N = 216/control group, N = 386). The prevalence of antipsychotic polypharmacy at follow-up was not significantly different between treatment settings when adjusting for differences in case-mix (P = 0.07). CONCLUSION: This multifaceted educational intervention failed to reduce the frequency of antipsychotic co-prescribing, but it suggested that future efforts to improve prescribing practice should address organizational barriers to implementation.