Limited information is available on the frequency of the many CYP2D6 alleles found in African-Americans. DNA was isolated and genetic testing was performed on samples from 222 African-Americans, healthy controls (n=131), and psychiatric patients (n=91). Each DNA was tested for CYP2D6 alleles *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14, *15, *17, *18, *19, *20, *25, *26, *29, *30, *31, *35, *36, *37, *40, *41 and *43 and 8 multiple copy alleles (*1xn, *2xn, *4xn, *41xn, *2Lxn, *17xn, *35xn and *10xn) using the AmpliChip CYP450 prototype microarray assay, along with allele-specific-PCR and PCR restriction fragment length polymorphism methods. No significant difference was noted between controls and psychiatric patients in any CYP2D6 allele frequencies. Three subjects were genotyped as poor metabolizers (1.4%; 0.0-2.9%, 95% confidence intervals (CI)), and 10 were classified as ultrarapid metabolizers (4.5%; 1.8-7.2%, 95% CI). A new CYP2D6 allele (*58) and two new duplicated CYP2D6 alleles (*17xn and *2Lxn) not previously reported were also identified. The frequency of the CYP2D6 overexpression in African-Americans may represent a greater therapeutic challenge than its deficiency based on these results. The most common alleles found in African-Americans including CYP2D6*1, *17 and *41 need to be investigated more closely for race-specific allelic variations and the mechanism responsible for differences in allele function more closely examined. The diversity of CYP2D6 alleles suggests that nucleotide arrays or similar methods are needed to efficiently test for the most prominent/relevant CYP2D6 alleles in humans.