OBJECTIVE: To compare persistence, compliance, and psychiatric treatment costs in patients initiating atypical therapies. METHODS: Medical and pharmacy claims data were used to compare persistence (days of therapy between first and last prescription, allowing therapy gaps <90 days); compliance (days of medication supplied with total days on therapy); and treatment costs in schizophrenic adults with claims for atypicals from March, 2001 to August, 2003 and enrollment for ?six-months before and ?12 months after therapy initiation. One-year psychiatric treatment costs were examined before and after therapy initiation. Differences in cost fluctuations were tested by univariate techniques. RESULTS: Persistence was approximately 30 days longer for patients receiving ziprasidone (n=217; 228 days) than risperidone (n=831; 193 days) or olanzapine (n=762; 201 days). Compliance was significantly (P<0.01) higher among patients receiving ziprasidone (87%) compared with other treatments (78%–80%). Ziprasidone patients had significantly larger decreases (—$6866) in mean annual psychiatric-related costs following therapy initiation than those on risperidone (—$3353; P=0.0116) or olanzapine (—$4764; P=0.0021). The primary driver of cost savings was reduced hospitalization after treatment initiation. CONCLUSION: Patients initiated on ziprasidone had longer persistence, better compliance, and greater decreases in psychiatric-related costs than those initiated on other atypicals.