This is an open-label (identity and dose of study drug will be known to patients), safety and pharmacokinetic study of the highest dose (150 mg equivalent) of paliperidone palmitate (referred to as study drug) administered by intramuscular (IM) injection (injection into the muscle) in patients with schizophrenia. A total of at least 200 adult patients with schizophrenia will participate in the study. The study will consist of 2 phases: an up-to-21-day screening period and a 53-week open-label treatment period including an end of study/withdrawal visit. The total duration of the study will be approximately 56 weeks. At the screening visit, if a patient has been treated with an antipsychotic medication before study entry, the medication may be continued during the study except for protocol-specified medications that are not permitted. If patients have not received previous treatment with at least 2 oral (by mouth) doses of the antipsychotic agents risperidone or paliperidone or 1 dose of injectable RISPERDAL CONSTA or paliperidone palmitate, they will undergo a 4-day evaluation period and receive a 6 mg/day oral dose of an extended-release (ER) formulation of paliperidone to evaluate their ability to tolerate study drug. Patients who are able to tolerate study drug and meet all other entry criteria for the study will then be administered a single IM injection into the deltoid muscle (upper arm) of paliperidone palmitate 150 mg equivalent (eq) on Day 1 (Treatment A). Patients who tolerate Treatment A will receive a 2nd IM injection in the deltoid muscle of 150 mg eq on Day 8 followed by 150 mg eq administered by IM injection in the deltoid or gluteal (buttocks) muscle once every 4 weeks for the remainder of the 53-week treatment period. Patients who do not tolerate Treatment A or who do not wish to have multiple blood samples collected for pharmacokinetic testing will be assigned to Treatment B. Patients who do not tolerate Treatment A will receive a single IM injection of study drug 100 mg eq at their next scheduled visit followed by a flexible dose schedule of study drug ranging from 50 to 150 mg eq administered by IM injection in the deltoid or gluteal muscle every 4 weeks for the remainder of the 53-week treatment period. Blood samples for pharmacokinetics (ie, to test the concentration of study drug in the blood) will be collected at specified times before and after each dose of study drug from all patients; additional blood samples for pharmacokinetic testing will be collected from patients receiving Treatment A. An additional blood sample may also be collected at any time during screening or before the first day of IM administration of study drug for patients who agree to participate in an optional part of the study called a pharmacogenomic evaluation (genetic testing) for possible use in characterizing the safety and/or efficacy of study drug in relation to the pharmacogenic (genetic) profile of the patient. Periodically during the study, patients will be assessed for the presence of psychiatric symptoms and severity of symptoms. The safety and tolerability of paliperidone will be evaluated by monitoring adverse events (side effects) and relevant changes in laboratory values, electrocardiogram (ECG), vital signs measurements, physical examinations, and extrapyramidal symptoms (ie, symptoms that can be associated with taking antipsychotic drugs) scores reported from the time of screening to the end of the study (Day 372 or at the time of the patient's early termination from the study). The concentration of paliperidone in plasma (colorless portion of blood) from blood samples collected from Day 1 through to the end of the study will also be determined. Since only limited information exists regarding the repeated administration of doses of paliperidone palmitate, an internal review board will meet 2 times during the study to review safety data collected. The first review of safety data will be performed after approximately 30 patients complete 99 days of treatment and the second review of safety data will be made after approximately 75 patients complete 176 days of treatment. After each review of safety data, the safety review board will make a recommendation to continue the study, modify the protocol, or to terminate the study. Patients will receive 1 injection in the deltoid muscle of Treatment (Tx) A (study drug 150mg eq) on Day 1. Patients will then receive 1 injection in the deltoid muscle of Tx A on Day 8 followed by 1 injection every 4 weeks in the deltoid or gluteal muscle OR patients will be assigned to Txt B and receive 1 injection in the deltoid or gluteal muscle of study drug 100mg eq at next visit followed by 1 injection every 4 weeks of study drug 50 to 150mg eq in the deltoid or gluteal muscle.