OBJECTIVE To test association of dopamine receptor D3 (DRD-3) gene polymorphisms with olanzapine response in genetic samples from a registration phase clinical trial. METHODS Eighty-eight acutely ill patients with schizophrenia or schizoaffective disorder were genotyped for ser-9-gly (rs6280) and 23 other polymorphisms within the DRD-3 gene. Allelic association of clinical response (mean baseline- to-endpoint reduction in Positive and Negative Syndrome Scale [PANSS] total and subscores) over 6 weeks of olanzapine treatment was assessed using repeated measures analysis of variance. RESULTS Ser-9-gly genotypes were associated with differences in PANSS total score improvement from baseline to 6 weeks (p = 0.021). This association was most notable for improvement in positive symptoms (p = 0.0001), with patients with gly/gly genotype significantly more responsive. More patients with the gly/gly genotype had greater positive symptom remission (endpoint rating of minimal or none on all PANSS positive items, 39.1%) compared with patients with gly/ser and ser/ser genotypes (13.8%; p = 0.033). DRD-3 polymorphisms in disequilibrium with ser-9-gly were also significantly associated with greater positive symptom improvement (p = 0.0009-0.021), and one not in complete linkage disequilibrium, with lesser improvement (p = 0.027). CONCLUSIONS Gly/gly DRD-3 genotype predicted statistically and clinically significantly better acute positive symptom reduction compared with other ser-9-gly genotypes in patients treated with olanzapine.