The highly polymorphic enzyme cytochrome P450 2D6 metabolizes about 20% of all drugs, including many antidepressants and antipsychotics. Individuals with mutant CYP2D6 alleles may be at increased risk for adverse drug reactions. We genotyped the CYP2D6 locus in 45 Puerto Rican psychiatry patients who had reported intolerance to antidepressants and/or antipsychotics. Three quarters of the group had at least one mutant allele. Twenty-one percent of the alleles had reduced activity, and eighteen percent were inactive. Two patients could not be genotyped by the microassay. Elevated basal metabolic index was common, except among patients who were homozygous extensive metabolizers. Compared to other populations that have been amply studied, Puerto Ricans may have relatively fewer inactive alleles and relatively more reduced-activity alleles.