The 5-HT(1B) receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B)) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR(1B) G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2, p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81, df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008; chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR(1B) G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies.