OBJECTIVES: To assess the effectiveness and economic impact of treatment with risperidone long-acting injection (RLAI) in patients with schizophrenia and matched patients prescribed conventional depot antipsychotics (CDA) using a naturalistic, retrospective chart review design. METHODS: Records were obtained for forty inpatients initiated on RLAI and 49 inpatients initiated on a CDA from March-June 2004 at the Alberta Hospital Edmonton. Discharge and readmission rates were evaluated after 1 year of treatment and a further pharmacoeconomic evaluation comparing global costs of treatment was completed 2 years post initiation. RESULTS: There were no statistically significant differences between the cohorts with respect to age, gender, number of previous psychiatric admissions and admission GAF scores. Post-discharge follow-up care was similar for both cohorts. After 1 year of treatment, discharge rates for RLAI and CDA were 83% and 58% and readmission rates were 0% and 26% respectively. After 2 years of treatment, discharge rates for RLAI and CDA were 87% and 66% and readmission rates 19% vs. 29% respectively. Mean days of hospitalization per patient over the second year of treatment was 73 days for RLAI and 171 days for CDA. Mean cost of treatment, including inpatient hospitalization and medication costs, was $57,414 per patient for RLAI and $123,975 per patient for CDA, representing a cost savings of $66,561 per patient per annum. All comparisons reached statistical significance (p<0.05). Secondary measures of effectiveness and tolerability revealed that treatment with RLAI was associated with a reduction in antipsychotic polypharmacy as well as a reduced need for anticholinergic rescue medications. CONCLUSION: In this difficult to treat patient population, RLAI conferred significant advantages over CDA in terms of effectiveness and tolerability. Differences in discharge and readmission rates, as well as an overall reduction in hospitalization, resulted in significant pharmacoeconomic advantages.