This 6-week, double-blind, placebo-controlled study evaluated paliperidone extended-release (ER) as both monotherapy and adjunctive therapy to mood stabilizers and/or antidepressants (MS/ADs) for schizoaffective disorder. Included subjects had a schizoaffective disorder diagnosis; a Positive and Negative Syndrome Scale (PANSS) total score of 60 or higher; a score of 4 or higher on 2 or more of the PANSS items for hostility, excitement, tension, uncooperativeness, or poor impulse control; and prominent mood symptoms (≥16 on the Young Mania Rating Scale and/or the 21-item Hamilton Rating Scale for Depression). Subjects were randomized to 6 mg/d paliperidone ER or placebo with flexible dosing (3-12 mg/d) until day 15. Randomization was stratified by use of MS/AD and study site. The primary analysis outcome was change in PANSS total score at week 6 last observation carried forward end point. A total of 311 subjects received paliperidone ER (n = 216) or placebo (n = 95); 52.0% received MS/AD. The mean (SD) modal dose of paliperidone ER was 8.6 (2.5) mg/d. Greater improvement was observed with paliperidone ER than placebo on mean (SE) PANSS total scores: -20.0 (1.3) and -10.8 (1.9), respectively. Subjects with prominent manic or depressive symptoms showed greater improvement with paliperidone ER versus placebo: mean (SE) Young Mania Rating Scale (-10.6 [0.9] vs -5.7 [1.2], respectively) and 21-item Hamilton Rating Scale for Depression (-10.2 [0.7] vs -6.2 [1.1], respectively). The most common adverse events with paliperidone ER were headache, akathisia, dizziness, insomnia, and dyspepsia. Paliperidone ER improved psychotic and affective symptoms both as monotherapy and as an adjunct to MS/AD. No new safety findings were observed in this population.