In this study we analyzed whether the polymorphisms 676T>G in the tumor necrosis factor receptor (TNFR) II gene and -308G>A in the TNFalpha promoter gene may influence the response grading to anti-TNFalpha therapy in rheumatoid arthritis. We enrolled and genotyped 105 RA patients treated with etanercept (n = 55), infliximab (n = 40) and adalimumab (n = 10) for 1 year. The clinical response was evaluated according to the ACR criteria every 3 months. Patients with TNFRII 676TG genotype was significantly associated with lower ACR response compared with 676TT genotype, at 3 (OR 3.78 95% CI 1.07-13.31) and 12 months (OR 4.30 95% CI 1.16-15.99) of treatment. No significant association between TNFalpha -308G>A polymorphism and the clinical response was found. TNFRII 676TG genotype is associated with a lower response to anti-TNFalpha therapy, independently from the specific agent used. This polymorphism could become a useful genetic marker for predicting the different response grading to anti-TNFalpha therapy.