Enzymes of catecholamine metabolism, plasma dopamine-beta-hydroxylase (DBH), and erythrocyte catechol-O-methyltransferase (COMT) were each previously shown to be transmitted as single codominant loci in a sample of approximately 30 multigenerational families that were analyzed with the single major locus model. Here, both major locus and polygenic hypotheses are tested by applying the mixed model of analysis to the identical samples, after breaking the families into two-generation units. For plasma DBH, the most parsimonious model is a dominant major locus (ie, high values dominant to low values) accounting for 41% of the variance and a polygenic component accounting for 25% of the variance. For erythrocyte COMT, the most parsimonious model is a dominant major locus accounting for 56% of the variance and a polygenic component accounting for 27% of the variance. The major locus for COMT has been supported by previous biochemical studies. The major locus for DBH is supported by the finding from our previous study of possible linkage to the ABO locus. Further biochemical and molecular genetic investigations are needed to better define the genetic loci determining the activity of these enzymes.