To investigate the possible role of the polymorphism located in the regulatory region of monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to rheumatoid arthritis (RA), a total of 141 Spanish RA patients and 194 controls, previously typed for human leukocyte antigen DRB1* (HLA-DRB1*), were genotyped for -2518 (A/G) MCP-1 gene polymorphism using polymerase chain reaction-restriction fragment length polymorphism. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to RA was found. Nevertheless, when patients and controls were stratified according to their HLA shared epitope (SE) status, a significant increase in the frequency of genotype GG was found among SE negative (SE-) patients with respect to both SE positive (SE+) patients and SE- controls (16% versus 4% in SE+ patients, pFisher=0.04, odds ratio [OR]=4.4, 95% confidence interval [95%CI]=1.03-21.48; and 4% in SE- controls, pFisher=0.02, OR=4.13, 95%CI=1.10-15.72). In conclusion, MCP-1 polymorphism is slightly associated with the susceptibility to RA in patients lacking the HLA SE.