The primary hypothesis is that, after an initial 150 mg eq. loading dose in the deltoid muscle followed by either deltoid or gluteal injections in patients with schizophrenia, paliperidone palmitate (25, 100, or 150 mg eq.) is superior to placebo as measured by the change in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) total score over a 13-week period.This is a randomized, double blind, placebo-controlled, parallel group, multicenter, dose-response study of men and women who have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia. The secondary objectives are to: Assess the benefits in personal and social functioning (key secondary endpoint) associated with the use of paliperidone palmitate compared with placebo, Assess the global improvement in severity of illness associated with the use of paliperidone palmitate compared with placebo, Assess the dose-response and exposure-response relationship of paliperidone palmitate The study includes a screening period of up to 7 days and a 13 week double-blind treatment period. The screening period includes washout of disallowed psychotropic medications. Subjects without source documentation of previous exposure to at least 2 doses of oral risperidone, or paliperidone ER, or one dose of i.m. RISPERDAL CONSTA, or paliperidone palmitate will be given 4 to 6 days of paliperidone ER 6 mg/day for tolerability testing. Patients who have source documentation of previous exposure to the above medications and are currently taking another antipsychotic regimen will continue their current treatment through Day -1. At the beginning of the double-blind treatment period, subjects will be randomly assigned in equal numbers to 1 of 4 treatment groups (an initial loading dose of 150 mg eq. of paliperidone palmitate given by deltoid injection followed by 3 fixed i.m. doses of paliperidone palmitate [25, 100, or 150 mg eq.] on Days 8, 36, and 64 or placebo given in the same manner). Note: The choice of the injection site (deltoid or gluteal) for all remaining injections after the initial loading dose will be at the discretion of the investigator. The entire study, including the screening period, will last approximately 14 weeks.Samples for pharmacokinetic (PK) evaluation will be collected at designated time points. Effectiveness and safety will be evaluated periodically throughout the study. A pharmacogenomic blood sample (10 mL) will be collected from patients who give separate written informed consent for this part of the study (where local regulations permit). This will allow for pharmacogenomic research, as necessary. Participation in pharmacogenomic research is optional. Approximately 105 to 115 mL of whole blood will be collected during the study. Patients randomly assigned to paliperidone palmitate will receive i.m. injections of paliperidone palmitate (150 mg eq. deltoid injection of paliperidone palmitate on Day 1, followed by 25, 100, or 150 mg eq. of paliperidone palmitate i.m. on Days 8, 36, and 64). Patients randomly assigned to placebo will receive a deltoid injection of placebo on Day 1 followed by placebo on Days 8, 36, and 64.