Real-world medication adherence and healthcare costs of patients with schizophrenia initiating long-acting injectable (LAI) vs. oral antipsychotics were compared. Patients with schizophrenia initiating LAI or oral antipsychotics (index event) were identified from MarketScan Commercial and Medicare claims databases and their medication possession ratios (MPR), pre- and post-index costs for inpatient/outpatient care were compared. Of 3,004 patients, 394 initiated LAI antipsychotics and 2,610 oral antipsychotics. Post-index, the mean MPR was greater for the LAI cohort (0.67 ± 0.34 vs. 0.56 ± 0.35; p < 0.001). Schizophrenia-related hospital costs for LAI users were reduced during the follow-up period in comparison to the pre-index period, but were increased for patients using oral antipsychotics (-$5,981 ± $16,554 vs. 758 ± 14,328, p < 0.001). The change in costs of outpatient care also favored LAI medications ($134 ± 8,280 vs. 658 ± 3,260, p = 0.023). Drug costs of LAI antipsychotics were higher ($4,132 ± 4,533 vs. 2,562 ± 2,714, p < 0.001). Schizophrenia patients initiating LAI antipsychotics incur less healthcare costs in comparison to patients initiating oral antipsychotics.