CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G-->A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f<1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP.