The inhibitory (NKG2A) and activating (NKG2D and NKG2C) natural killer (NK) cell receptors are expressed on a subset of NK and T cells. They regulate the innate and adaptive immune systems related to cytotoxicity and cytokine production that are involved in the pathogenesis of rheumatoid arthritis (RA). The role of inhibitory and activating NK cell receptor genes might contribute to chronic inflammation and destruction of bone and cartilage in RA. Therefore, we investigated the association of the NKG2A, NKG2C, and NKG2D genotypes with RA. NKG2A (KLRC1) NKG2C (KLRC2), and NKG2D (KLRK1, D12S249E) genes were genotyped in 210 unrelated patients with RA and 298 controls using a polymerase chain reaction-restriction fragment length polymorphism. We further investigated the relationships between the genotypes of each single nucleotide polymorphism and the presence of rheumatoid factor (RF), antinuclear antibody (ANA), and bony erosions in RA patients. The major NKG2A c.338-90*A/*A, NKG2C102*Ser/*Ser, and NKG2D72*Ala/*Ala genotypes in RA were significantly associated compared with controls [P = 0.013, odds ratio (OR) = 0.6, 95% confidence interval (CI) = 0.44-0.91; P < 0.0001, OR = 2.1, 95% CI = 1.44-2.96; and P = 0.019, OR = 0.6, 95% CI = 0.45-0.93, respectively]. The minor NKG2A c.338-90*G/*G, NKG2C102*Phe/*Phe, and NKG2D72*Thr/*Thr genotypes showed a risk of RA (P = 0.010, OR = 2.0, 95% CI = 1.17-3.54; P < 0.0001, OR = 0.2, 95% CI = 0.12-0.48; and P = 0.032, OR = 2.3, 95% CI = 1.05-5.01, respectively) compared with controls. No significance was observed between the inhibitory (NKG2A) or activating (NKG2C and NKG2D) receptor genotypes and the presence of RF, ANA, or bony erosions in RA.