The aim of this study was to investigate the CD69 gene as a new functional candidate gene for rheumatoid arthritis (RA) genetic predisposition. A case-control association study including 933 RA patients and 800 healthy individuals was conducted. Five haplotype-tagging single nucleotide polymorphisms (SNPs) (rs929615, rs3176806, rs4763299, rs11052877, and rs3176789) covering the CD69 gene coding, 5' and 3' untranslated regions were selected as CD69 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. No statistically significant differences were observed in the single marker association study with regard to either genotypic or allelic frequencies when considering the rs929615, rs3176806, rs4763299, rs11052877, and rs3176789 CD69 SNPs independently. According to these findings, no statistically significant skewing was observed between the RA patients and the controls in the distribution of CD69 haplotypes. In summary, our results do not support a major role for the CD69 gene polymorphisms in RA genetic predisposition in our population.