Objective: Rheumatoid Arthritis (RA) is an autoimmune and chronic inflammatory disease of unknown etiology. Killer cell immunoglobulin-like receptors are expressed on the surface of natural killer cells and CD28null T-cells, both present in synovial membrane of RA. Therefore we evaluated the associations of KIR genes with RA. Methods: 16 KIR genes were genotyped in 100 healthy subjects (HS) and 100 RA patients fromWestern Mexico using PCR-SSP. Differences in KIR genotypes and gene frequencies were assessed using the X2 test. Results: Gene frequency of KIR2DL3 was lower in RA than in HS (p = 0.0019), whereas KIR2DL2 and KIR2DS2 were higher in RA than HS (p = 0.0004 and p = 0.0487, respectively). In addition were identified 38 genotypes (from G1-G38) in both studied groups, and the genotype frequencies of G1, G6 and G14 showed significant differences (p = 0.0001, p = 0.0208 and p = 0.0300, respectively). Conclusions: The presence of KIR2DL2, KIR2DS2 and absence of KIR2DL3 are associated with RA. Moreover, two genotypes BX are associated with RA. These results suggest that KIRs can be involved in RA susceptibility.Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México. Doctorado en Ciencias Biomédicas, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México. Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México.