The CYP2D6 liver enzyme, which metabolizes 25-30% of common medications, is highly polymorphic. Existing studies of Hispanics have focused on Mexicans and Mexican-Americans. The goal of the study was to identify the CYP2D6 alleles associated with reduced or negligible activities present in the Puerto Rican population.The study cohort comprised 40 Puerto Rican psychiatric patients referred because of suspected intolerance of drugs metabolized by CYP2D6, and five subjects without suspected adverse responses to these drugs. All subjects had both parents and all grandparents born in Puerto Rico. Genomic DNA was queried for 27 CYP2D6 alleles using the Roche AmpliChip P450 test.A total of 12 alleles were identified. The most common alleles were CYP2D6*1 > *2 > *4 > *41. The inactive alleles were *4 > * 5 > * 31 >*40; reduced activity alleles were *10 >* 17 > *9* = *29; active alleles were *1 > *2 > *35. Two subjects carried the rare *31 allele. Only one subject carried two non-functional alleles (CYP2D6*5/*40), and was predicted to be a poor metabolizer.Any conclusions should be interpreted with caution given the small population sample investigated. Nonetheless, our findings strongly suggest that Puerto Ricans exhibit distinct CYP2D6 allele frequencies and harbor a non-functional allele that is rare or absent in other populations and are highly valuable for the emerging practice of Personalized Medicine in admixed populations like Puerto Ricans.