Objective<br>Assess association between adherence and persistence with second-generation oral antipsychotics (SGOAs), psychiatric-related relapse and healthcare utilization among patients with schizophrenia experiencing two or more psychiatric-related relapses.<br>Methods<br>A retrospective analysis of the US Medicaid Multi-State Database for 2004–2008. Patients with schizophrenia (aged 18–64) with two or more psychiatric-related relapses within 1 year after SGOA initiation were selected. Associations between a dichotomous measure of adherence and persistence with SGOAs and psychiatric-related relapse and healthcare utilization were assessed using unadjusted and covariate-adjusted regression models. No adjustment was made for multiplicity.<br>Key findings<br>Study cohort consisted of 3714 patients with mean age of 42.6 years. Overall, 45% of patients were adherent and 50% persistent with SGOAs. Unadjusted and covariate-adjusted analysis results suggested the 12-month psychiatric-related relapse rate was lower among adherent/persistent patients versus non-adherent patients (unadjusted mean: 3.85 versus 4.13; P?<?0.001; covariate-adjusted incident rate ratio (IRR): 0.90; 95% confidence interval (CI): 0.86–0.94) and non-persistent patients (unadjusted mean: 3.81 versus 4.21; P?<?0.001; covariate-adjusted IRR: 0.88; 95%CI: 0.84–0.92). Compared with non-persistent patients, persistent patients had significantly lower rates of all-cause inpatient admissions (IRR: 0.87; 95%CI: 0.82–0.93) and emergency department visits (IRR: 0.78; 95%CI: 0.73–0.85).<br>Conclusions<br>Although SGOAs have proven efficacy in lowering the rate of psychiatric-related relapses, lower adherence and persistence rates may be an inhibiting factor in achieving optimal benefits from SGOAs. Future research is needed to assess whether newer antipsychotics with less-frequent dosing may improve adherence among patients with schizophrenia.