OBJECTIVE To examine medication adherence and discontinuation in two separate groups of patients with schizophrenia or bipolar disorder (BD), who began receiving a long-acting injectable antipsychotic (LAI) versus those who changed to a different oral antipsychotic monotherapy. METHODS The Truven Health Analytics MarketScan Multi-State Medicaid claims database was used to identify patients with schizophrenia; Truven Health Analytics MarketScan Commercial and Medicaid claims databases were used to identify patients with BD. The analyses included adult patients (≥18 years) who either began receiving an LAI (no prior LAI therapy) or changed to a different oral antipsychotic (monotherapy). The first day of initiating an LAI or changing to a new oral antipsychotic was the index date. Linear and Cox regression models were conducted to estimate medication adherence (proportion of days covered [PDC]) and time to medication discontinuation (continuous medication gap ≥60 days), respectively. Models adjusted for patient demographic and clinical characteristics, baseline medication use, and baseline ED or hospitalizations. RESULTS Patients with schizophrenia (N = 5638) who began receiving LAIs had better medication adherence (5% higher adjusted mean adherence) during the 1 year post-index period and were 20% less likely to discontinue their medication during the entire follow-up period than patients who changed to a different oral antipsychotic monotherapy, adjusting for differences between LAI users and oral users. Similarly, patients with BD (N = 11,344) who began receiving LAIs also had 5% better medication adherence and were 19% less likely to discontinue their medication than those using oral antipsychotics. CONCLUSIONS Clinical differences unmeasurable in this database may have been responsible for the choice of LAI versus oral antipsychotics, and these differences may be responsible for some of the adherence advantages observed. CONCLUSIONS This real-world study suggests that patients with schizophrenia or BD who began receiving LAIs had better medication adherence and lower discontinuation risk than those who changed to a different oral antipsychotic monotherapy.