Rheumatoid arthritis (RA) in Thai population is significantly associated with HLA-DR4 shared epitope (SE) alleles, particularly with DRB1*0405 (P = 0.00004, OR = 3.84, 95% CI = 1.93, 7.7). In addition, tumor necrosis factor-alpha (TNF-alpha) gene -863A alleles were found to be significantly increased in 77 RA patients compared to 162 healthy controls (P = 0.03, OR = 1.73, 95% CI = 1.05, 2.87). Interestingly, TNF-863 AC and SE have a synergistic effect on the susceptibility to RA. The OR for the presence of both risk factors (DR4 SE and -863 AC) was cumulative: 15.4 (95% CI = 3.75, 73.6) while the separate OR of DR4 SE and -863 AC were 3.84 and 2.36, respectively. The TNF was not associated with the clinical manifestation and severity of Thai RA patients. However, a highly significant association was found between RF positivity, one marker for severity, and RA patients with DR4 SE (P = 0.0005, OR = 9.42, 95% CI = 2.26, 45.27).