Individuals with certain HLA class I genotypes are highly susceptible to disease after viral infection. Natural killer (NK) cells kill virus-infected cells through a mechanism involving HLA class I receptors. These facts may be connected if an individual's HLA genotype regulates the number and function of NK cells. We have observed that subjects homozygous for the HLA-B/C region of conserved major histocompatibility complex (MHC) extended haplotypes have lower NK cell activity and a significantly lower frequency of CD16+CD56+ NK cells than heterozygotes. The proportion of CD16-CD56+ NK cells was unaffected by zygosity for the HLA-B/C region. We show here that the frequency of CD16+CD158b+, but not CD16-CD158b+ NK cells, was significantly lower (p <0.026) in homozygotes for HLA-Cw7 (NKI ligand) haplotypes than in heterozygotes. The frequencies of CD16+CD158a+ and CD16-CD158a+ and CD16-CD158a+ or CD16+NKB1+ and CD16-NKB1+ NK cells were not different in these donor groups. These findings suggest that the proportion of NK cells coexpressing CD16 and CD158b, but not CD158a nor NKB1, is influenced by zygosity for the HLA-Cw7 (NK1 ligand) haplotype. Since NK cells are involved in protection from virus infection, a reduced size of a ligand-specific NK subset in individuals homozygous for some HLA-B/C haplotypes may help explain their increased susceptibility to virus-induced diseases.