Recent studies have examined the relationship between polymorphic alleles of the MDR1 gene and the course of HIV. Such polymorphisms may alter the metabolism of antiretroviral medications or influence susceptibility to HIV infectivity. We therefore studied a polymorphism in MDR1 (C3435T), and the CYP3A4*1B variant allele, the latter of which has not been previously studied in HIV. Ninety-six patients of either Ethiopian (57) or Caucasian (39) ethnicity and 276 controls were studied including serial CD4 counts, clinical course, and AIDS-defining illnesses. For both ethnic groups, the C allele of MDR1 C3435T was highly associated with being infected with HIV (p < 0.0001) compared to controls, but genotype did not influence change in CD4 counts over time in the patients, whether or not they were treated with antiretrovirals. CYP3A4*1B was also significantly associated with being infected with HIV (p < 0.0001) both in heterozygotes and in homozygotes for the polymorphism, but only for Ethiopians (p < 0.023 compared to Caucasians, p = 0.44). CYP3A4*1B did not influence CD4 count or AIDS defining illnesses. We conclude that in Israeli patients, polymorphisms in drug metabolism and disposition genes may influence infectivity of HIV but do not influence the course of the disease. Larger studies are needed to confirm these findings.