OBJECTIVE: To compare effectiveness and tolerability outcomes of patients with schizophrenia treated with risperidone long-acting injection and patients treated with conventional depot antipsychotics. METHODS: Patients initiated on risperidone long-acting injection during a four-month index period were compared to patients initiated on a conventional depot antipsychotic during the same time period. Patient demographics including age, gender, diagnosis, number of previous psychiatric admissions and in-patient program were evaluated. The effectiveness outcomes of antipsychotic polypharmacy, discharge and readmission rates were compared. Neurological tolerability was assessed as measured by the prescribing of regularly scheduled anticholinergic rescue medications. RESULTS: Forty patients initiated on risperidone long-acting injection were compared to 49 patients initiated on a conventional depot antipsychotic. The two patient groups were demographically very similar. The risperidone long-acting injection group was 75% male with an average age of 41-years and 6.0 previous psychiatric admissions. The conventional depot group was 67% male with an average age of 47.5 years and 5.9 previous psychiatric admissions. Antipsychotic polypharmacy was reduced from 63% to 31% in the risperidone long-acting injection group but increased from 29% to 73% in the conventional depot group. The use of anticholinergic rescue medications decreased from 47% to 12% in the risperidone long-acting injection group but increased from 31% to 73% in the conventional depot group. After 12-months of observation, 83% of the risperidone long-acting injection patients had been discharged and none had been readmitted, whereas 58% of the conventional depot group had been discharged and, of those, 26% had already been readmitted. CONCLUSION: In this difficult-to-treat population of patients, risperidone long-acting injection conferred significant advantages over conventional depot antipsychotics in terms of effectiveness and tolerability. As well, the substantial differences in discharge and readmission rates infer considerable pharmacoeconomic advantages in favor of risperidone long-acting injection.