Schizophrenia and bipolar disorder, although diagnostically separate, likely share elements of their genetic etiology. This study assessed whether the COMT Val158Met polymorphism has shared or specific associations with clinical phenotypes evident in schizophrenia and bipolar disorder. Schizophrenia and bipolar patients completed a clinical assessment encompassing premorbid functioning and current and lifetime symptomatology. Multivariate analyses yielded a three-way interaction of diagnosis, COMT genotype for lifetime symptomatology. The COMT Val allele was associated with greater positive symptomatology in schizophrenia, whereas Met homozygosity was associated with greater positive symptomatology in bipolar disorder. Findings support the COMT Val158Met polymorphism conferring vulnerability for different clinical phenotypes in schizophrenia and bipolar disorder. Lifetime symptomatology may be particularly useful in determining the relationship between genes and clinical phenotypes across mental disorders.