Catechol-O-methyltransferase (COMT) Val158Met polymorphism has been identified as a potential etiologic factor in schizophrenia. It has been proposed that this polymorphism could be associated with specific clinical markers. The aim of the study was to evaluate the influence of COMT Val158Met polymorphism genotype in the phenotypic expression of first episode psychosis at onset. Age of onset, DUP, SANS, and SAPS (positive, disorganized, and negative dimensions) were studied in 169 Caucasian drug-naïve patients with a first-episode of non-affective psychosis. The COMT Val158Met polymorphism was typed using PCR amplification of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with COMT and gender as independent variables. Patients with Val/Val genotype had significantly higher levels of SANS negative dimension scores (F: 3.539; P = 0.031) and had a younger age of onset (F: 4.649; P = 0.011) than Met carriers. Our findings suggest that the Val allele is associated with onset phenotypic features related to a poor prognosis of the illness. These data would indicate that COMT genotype may have a role in the etiological model for schizophrenia and other psychotic disorders. © 2007 Wiley-Liss, Inc.