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Despite its importance in drug metabolism and disease susceptibility, CYP2D6 activity and genetic polymorphism have rarely been investigated in African-American populations. In order to bridge this gap, we examined the genotype and phenotype of the enzyme in 154 African-American (AA) and 143 Caucasian (C) normal volunteers. AAs are significantly more likely to possess * 17 and * 5, but less likely to have * 4. Overall, the two groups were similar in their CYP2D6 activity as measured with dextromethorphan as the probe (metabolic ratio 2.21 ± 0.78 for AAs; 2.11 ± 0.86 for Cs; t = 1.02, NS). Two of four AAs and six of seven Cs were classified as poor metabolizers and have two nonfunctioning alleles. CYP2D6 activity is determined by * 17, * 4, * 5 and age in AAs (r2 = 0.33, f = 18.8, P< 0.001) and by * 4 and * XN in Cs (r2 = 0.14, f = 10.8, P< 0.001). These results support previous findings demonstrating the importance of * 17 in determining CYP2D6 activity in AAs.