Controversial observations have been published on the association of the cytotoxic T lymphocyte associated antigen gene's variants with rheumatoid arthritis (RA). After genotyping 428 patients and 230 matched controls, the prevalence of the CT60(∗)G allele was more frequent in RF- and/or anti-CCP-seropositive RApatients, compared to the healthy controls (P < .001). Regression analysis revealed that the CT60(∗)G allele is a possible predisposing factor for RA in these subgroups. No accumulation of the +49(∗)G allele was found among patients, and this variant was not found to correlate with RA. Assaying the possible genotype variations, the +49(∗)G-CT60(∗)G allelic combination was accumulated in seropositive RA-subtypes, and was associated with the risk of RA (OR = 1.73, P = .001 for the whole RA-population). Although the +49(∗)G allele did not mean a predisposition to RA alone, in combination with CT60(∗)G it, also conferred risk, suggesting that the +49A/G variant is associated with the risk of RA only in certain haplotypes.