The beta-chemokine receptor CCR5 is required as a coreceptor by non-syncytium-inducing (NSI) strains of human immunodeficiency virus type 1 (HIV-1). NSI viruses predominate early during an infection and are thought to be important for the transmission of HIV-1. The importance of CCR5 during parenteral transmission of HIV-1 was investigated. The distribution of the homozygous deleted CCR5 genotype among 566 exposed persons with hemophilia and 97 exposed transfusion recipients indicated that the lack of CCR5 expression protected persons from infection. This suggests that the initial predominance of NSI viruses during an infection does not result from limited availability of CXCR4-expressing cells within the mucosa but rather implies a more fundamental requisite for CCR5-expressing cells early during an infection regardless of the route of transmission. In addition, no difference in the rate of progression to AIDS (CDC 1987 definition) of infected heterozygous compared with homozygous wild type subjects was observed.