We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [−5.2 (21.5)] and PP 100 mg eq. [−7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p⩽0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p⩽0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56–71%), mild (24–39%), moderate (2–12%), or severe (0–2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.