OBJECTIVE: To evaluate the effectiveness and tolerability of risperidone long-acting injection (RLAI) as compared to the usual treatment alternative of conventional depot antipsychotics. METHODS: Patients initiated on RLAI during the four-month period of March 2004 through June 2004 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 anticholinergic side-effect medications. RESULTS: Forty patients initiated on RLAI were compared to 49 patients initiated on a conventional depot antipsychotic. The two patient groups were demographically similar. The RLAI 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. All patients in each group were diagnosed with schizophrenia. Antipsychotic polypharmacy was reduced from 63% to 31% in the RLAI group but increased from 29% to 73% in the conventional depot group. The use of anticholinergic side-effect medications decreased from 47% to 12% in the risperidone RLAI group but increased from 31% to 73% in the conventional depot group. After ten-months, 83% of the risperidone RLAI patients had been discharged and none had been readmitted, whereas only 58% of the conventional depot group had been discharged with 26% having been readmitted. CONCLUSIONS: In this difficult-to-treat population of patients, risperidone RLAI conferred significant advantages over conventional depot antipsychotics in terms of effectiveness and tolerability. As well, the substantial differences in discharge and readmission rates create considerable pharmacoeconomic advantages in favor of RLAI.