The aim of this study was to perform a systematic review of the effects of 1-month paliperidone palmitate (PP1M) for the treatment of schizophrenia and related psychotic disorders in terms of outcomes reported in real-world evidence studies. A systematic review of real-world randomized and nonrandomized studies with PP1M was performed and is reported according to PRISMA guidelines. Comparative effectiveness data with oral antipsychotics indicate that PP1M has a lower likelihood of relapse-related events, including rehospitalization, and these differences are clinically relevant. A randomized, double-blind study showed that PP1M has no advantage over haloperidol decanoate in the time to treatment failure. Although there was a marked variability across studies, PP1M was not superior to other antipsychotics in terms of study completion rates. Pharmacoeconomic data show that, during a follow-up period of 12 months, the mean total healthcare cost was not significantly different in patients treated with PP1M compared with those receiving oral antipsychotics. The mean maximum prolactin levels were significantly higher with PP1M than with haloperidol decanoate; however, neither drug differs in the frequency of prolactin-related adverse events. Results on prolactin-related adverse events were inconsistent in two randomized comparisons with oral antipsychotics and were not reported in a randomized comparison with aripiprazole. There were no significant differences between haloperidol decanoate and PP1M in the severity of abnormal involuntary movements and parkinsonism, or in the incidence of tardive dyskinesia; however, patients treated with haloperidol decanoate showed greater worsening of akathisia and required treatment for parkinsonism and akathisia significantly more frequently than patients who received PP1M. In conclusion, real-world data that originate from both pragmatic randomized clinical trials and observational studies indicate that PP1M is superior to oral antipsychotics in delaying the time to relapse or treatment failure. Furthermore, the pharmacoeconomic data reviewed for this article suggest that the advantages of PP1M compared with oral antipsychotics are not associated with an increased total cost for healthcare providers.