OBJECTIVE: To evaluate whether 6-, 9-, and 12-month rates of persistency (long-term compliance) with initially prescribed antipsychotic monotherapy translate into cost savings. METHODS: We identified 220 newly diagnosed psychotic patients from approximately 180 managed-care organizations who were initiated on quetiapine monotherapy during an 18-month period. Patients were randomly selected and matched by study date to populate three comparator groups: a haloperidol group, a risperidone group, and patients initiated on any atypical agent except quetiapine. Patients were tracked for at least one year to identify whether they remained on monotherapy, added to the therapy, switched, or discontinued it. Psychiatric costs were aggregated by service type. Analyses included tests of proportions for rates, Cox proportional hazard models for time, and linear regressions for cost. RESULTS: At six months, 62.73% of quetiapine patients remained on monotherapy vs 33.51% of haloperidol patients (p < .01), 44.60% of risperidone patients (p < .01), and 41.57% of the composite cohort (p < .01). At nine months, 47.73% of quetiapine patients remained on monotherapy vs 23.71% of haloperidol patients (p < .01), 38.97% of risperidone patients (p = 0.06), and 32.78% of the composite cohort (p < .01). At one year, 35.45% of quetiapine patients remained on monotherapy vs 13.40% of haloperidol patients (p < .01), 31.46% of risperidone patients (p = 0.37), and 26.13% of the composite cohort (p = 0.01). All three comparisons were statistically different; median values were 220 days for quetiapine, 90 for haloperidol (p < .01), 159 for risperidone (p = 0.02), and 141 for the composite cohort (p < .01). Annual costs were reduced by $4.39 per additional day (p < .01) of persistency with the initially prescribed antipsychotic. Combining multivariate results shows cost savings for quetiapine of $570.70/year per patient compared with haloperidol, $250.23/year per patient compared with risperidone, and $307.30 if quetiapine were the atypical antipsychotic of first choice. CONCLUSION: When quetiapine is the first-line therapeutic choice, more patients remain compliant, and cost savings result.