F17464, a highly potent preferential D3 antagonist, is a novel compound in development for schizophrenia treatment. This phase II, double-blind, randomized, placebo-controlled, parallel-group study in five European countries evaluated the efficacy and safety of F17464, 20 mg twice daily, versus placebo over 6 weeks in patients with acute exacerbation of schizophrenia. Change from baseline to Day 43 of the Positive and Negative Syndrome Scale (PANSS) total score was the primary outcome. The data from 134 randomized patients (67 per group) were analyzed (efficacy/safety). Using analysis of covariance (ANCOVA) after last observation carried forward (LOCF) imputation (primary analysis), the PANSS total score reduction was statistically significantly greater for F17464 than placebo treated subjects at endpoint (p = 0.014); using ANCOVA with Multiple Imputation (MI) method, the between-group difference was in favor of F17464 but did not reach statistical significance. Differences in PANSS positive and general psychopathology subscale score, Marder positive factor score, PANSS response, and PANSS resolution criteria were also statistically significant in favor of F17464 (p values < 0.05) using the LOCF method, with similar results as for the primary analysis using the MI method. Treatment-related adverse events (AEs) were reported in 49.3% and 46.3% of patients on F17464 and placebo, respectively. The most common AEs in F17464 group: insomnia, agitation, and increased triglycerides; worsening of schizophrenia/drug ineffective was less frequent in F17464. Interestingly, no weight gain, no extrapyramidal disorder except rare akathisia were observed under F17464. This 6-week trial demonstrated therapeutic efficacy of 40 mg/day F17464 in improving symptoms of acute exacerbation of schizophrenia with a favorable safety profile.