Inconsistencies in the relation between COMT variation and schizophrenia may be clarified by careful delineation of a target phenotype. The present study reports a significant association between a COMT haplotype and the severity of manic symptoms in 162 patients with schizophrenia or schizoaffective disorder (SZ). These data suggest that the effect of COMT variation may be associated with comorbid manic symptoms in SZ.