The introduction of tumour necrosis factor antagonists (anti-TNF) has greatly improved the treatment of rheumatoid arthritis, however, a significant proportion of patients fail to respond to therapy. We hypothesized that variants spanning the type 2 TNF receptor (TNFR2) and the TNF cleavage enzyme (TACE) genes contribute towards the observed variation in patient response (defined as the absolute change in 28-joint count disease activity score). Twenty-nine single nucleotide polymorphisms (SNPs) were genotyped in a large cohort of patients (n=602) and analysed by multivariate linear regression. Three SNPs (rs520916, rs652625, rs597519) mapping upstream of TNFR2 showed borderline evidence for association (P<0.1) across the complete cohort and, more so, in the etanercept-treated subgroup. However, the evidence of association was neither replicated in an independent cohort (n=377) nor strengthened after combined analysis (n=979). We conclude that common SNPs spanning the TNFR2 and TNF cleavage enzyme (TACE) genes do not have a major effect on the response to anti-TNF therapy in rheumatoid arthritis patients.