Levels of the enzyme dopamine beta-hydroxylase (DbetaH) in the plasma and cerebrospinal fluid (CSF) are closely related biochemical phenotypes. Both are under strong genetic control. Linkage and association studies suggest the structural gene encoding DbetaH (locus name, DBH) is a major locus influencing plasma activity of DbetaH. This study examined relationships of DBH genotype determined at two polymorphic sites (a previously described GT repeat, referred to as the DBH STR and a single-base substitution at the 3' end of DBH exon 2, named DBH*444 g/a), to CSF levels of DbetaH protein in European-American schizophrenic patients, and to plasma DbetaH activity in European-American patients with mood or anxiety disorders. We also investigated linkage disequilibrium (LD) between the polymorphisms in the pooled samples from those European-American subjects (n=104). Alleles of DBH*444 g/a were associated with differences in mean values of CSF DbetaH levels. Alleles at both polymorphisms were associated with plasma DbetaH activity. Significant LD was observed between respective alleles with similar apparent influence on biochemical phenotype. Thus, allele A3 of the DBH STR was in positive LD with DBH*444a, and both alleles were associated with lower plasma DbetaH activity. DBH STR allele A4 was in positive LD with DBH*444 g, and both alleles were associated with higher plasma DbetaH activity. The results confirm that DBH is a major quantitative trait locus for plasma DbetaH activity, and provide the first direct evidence that DBH also influences CSF DbetaH levels. Both polymorphisms examined in this study appear to be in LD with one or more functional polymorphisms that mediate the influence of allelic variation at DBH on DbetaH biochemical phenotypic variation