Natural killer (NK) cells are important antiviral effectors of innate immunity because of their contribution to virus elimination. NK cell-mediated immunological reaction to hepatitis B virus (HBV) infection depends on a fine balance between inhibitory and activating receptors. The aim of the study was to investigate genetic polymorphisms in NK cell receptors (NKR)—KLRD1 (CD94), KLRK1 (NKG2D), KLRC4 (NKG2F), and KLRC1 (NKG2A)—to evaluate the association of NKR genetic polymorphisms with susceptibility to chronic hepatitis B in a Han Chinese population. Twelve single nucleotide polymorphisms (SNPs), including rs2302489 in CD94; rs2255336, rs2617160, rs7980470, rs 2734565, and rs17513986 in NKG2D; rs2617170, rs17549004, and rs3825295 in NKG2F; rs2734414, rs7301582, and rs2734440 in NKG2A, were selected in the present study. SNP genotyping was undertaken in 500 Han Chinese patients (285 patients with chronic hepatitis B and 215 patients who cleared HBV spontaneously) by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and by the TaqMan method. Single marker association analysis was conducted and the SNP rs2617160 with a TT genotype in NKG2D was associated significantly with an increased risk of chronic hepatitis B (P = 0.044; OR = 1.49; 95% CI = 1.01–2.19). Haplotype analysis with multiple loci indicated that there was no significant association between the haplotypes of the NKR genes and susceptibility to chronic hepatitis B. The SNP rs2617160 in NKG2D associated with susceptibility to chronic hepatitis B in a Han Chinese population. J. Med. Virol. 82:1501–1507, 2010. © 2010 Wiley-Liss, Inc.