Extended-release intramuscular paliperidone palmitate (Xeplion®; Invega® Sustenna®) [henceforth referred to as intramuscular paliperidone palmitate] is a long-acting injectable (LAI) formulation of the well established atypical antipsychotic agent paliperidone (9-hydroxyrisperidone), which is the major active metabolite of risperidone. This article reviews, from an EU perspective, the therapeutic efficacy and tolerability of intramuscular paliperidone palmitate in the treatment of adults with schizophrenia, and the pharmacology of paliperidone that is relevant to the intramuscular formulation. Intramuscular paliperidone palmitate 25-150 mg equivalents (mg eq.) effectively reduced symptoms of schizophrenia in most short-term (9-13 weeks) placebo-controlled trials, as demonstrated by improvements in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint that were significantly greater in intramuscular paliperidone palmitate than placebo recipients. The onset of clinical response was 8 days in patients who received the recommended initial 150 mg eq. dose of intramuscular paliperidone palmitate into the deltoid muscle on day 1. In a longer-term (24-week maintenance phase and variable length double-blind phase) placebo-controlled trial, intramuscular paliperidone palmitate was associated with a significantly longer time to relapse than placebo in patients with schizophrenia at a preplanned interim analysis conducted after 68 relapse events. Because of these favourable results, the study was terminated early. In two 13-week trials, one of which was conducted in Chinese patients, intramuscular paliperidone palmitate administered using the recommended initiation dosage regimen was noninferior to LAI-risperidone in patients with schizophrenia in terms of the between-group treatment difference (intramuscular paliperidone palmitate vs LAI-risperidone) for the mean change from baseline to endpoint in PANSS total score. The tolerability of intramuscular paliperidone palmitate was generally acceptable in clinical trials of schizophrenia. No new safety concerns were revealed compared with oral paliperidone, except for injection site-related reactions. In conclusion, intramuscular paliperidone palmitate is a useful option for the treatment of patients with schizophrenia.