This study aimed to investigate whether functional variants of endothelial nitric oxide synthase (eNOS) gene play any role in rheumatoid arthritis (RA) ethiopathogenesis and treatment in the Turkish population. Because, eNOS variants are responsible for alteration of the NO level in plasma, by reducing/increasing the endothelial NO synthesis. In the study, two eNOS gene variants (G894T and intron 4 VNTR A/B) were examined at extracted DNAs from 65 peripheral blood cell of RA patients. For the control, blood samples obtained from 70 healthy persons were studied. Genotyping of molecular variants was performed by PCR-RFLP and/or PCR technique. The data obtained was compared in itself and response to therapy. We found that "TT genotypic frequency" for the G894T variant was significantly associated with RA with an overall risk of 8.3-fold (p 0.029). No association was identified between intron 4 VNTR A/B variant and RA. At the 6 months, the mean visual analog scale (VAS), health assessment questionnaire (HAQ), and disease activity score for 28 joints (DAS 28) improvement was not significant among groups. Improvement in DAS was significantly better in anti-TNF treatment than disease-modifying antirheumatic drugs (DMARD) treatment treated subgroup. We report for the first time that variants in the eNOS "TT" genotype might be contributed to the increased risk of RA in the Turkish population. These results imply that functional variants of eNOS gene might have an effect on RA patients and response to anti-TNF treatment. In addition, the results suggest that eNOS variants might be associated and affect host susceptibility and/or response to treatment in Turkish RA patients.