Monoamine oxidases (A and B) are of great interest in connection with alcoholism. Low MAO activity has been found in the brains and the platelets of alcoholics and their relatives supporting the hypothesis that low MAO activity is a biological marker for vulnerability to misuse. In order to determine the role of the MAO genes in alcoholism we have measured MAO-B activity and typed two simple sequence repeats (one in the MAO-A gene and one in the MAO-B gene) in a sample of 133 unrelated alcoholics, 300 subjects from 30 two- and three-generation pedigrees ascertained through an alcoholic proband, and 92 normal controls. The unrelated alcoholic group did not differ in MAO-B activity from normal controls nor were there significant differences between subtypes. We did, however, find significant differences between alcoholic males and females (t = 2.836, p = .005), a difference that was not present in controls. A two-way analysis of variance of MAO-B activity as a function of the allelic variation of each marker locus and diagnosis among male subjects was performed. There was no evidence for mean differences in activity levels for different alleles. The distribution of MAO-A and MAO-B "alleles" in the alcoholic sample differed from that of the control sample. Affected sib pair linkage analysis of MAO genes and alcoholism showed no evidence for an excess of concordant affected sib pairs suggesting that this region of the X-chromosome does not harbor a susceptibility locus.