Expansion of CD4 + CD28 null , a common feature of immunosenescence, which has been reported in rheumatoid arthritis (RA) patients, may also be associated with a CD4 + imbalance. Although the increase of CD4 + CD28 null cells has been related to TNFα exposure, nothing is known about the possible role of genetic variants of this cytokine.Participants were genotyped for TNFA rs1800629 (−308 G>A) and frequency of the CD4 + CD28 null , regulatory T cells and Th1 cells subsets were quantified in peripheral blood samples by flow cytometry in 129 RA patients and 33 healthy controls.The expansion of CD4 + CD28 null cells in RA patients was associated with TNFA genotype, even at diagnosis, and linked to markers of aggressive disease in patient carriers of the minor allele. Analysis of regulatory T cells and IFNγ-CD4 + expression suggested that defective suppression and/or Th1-shift could underlie the expansion of this population in these patients. Finally, although treatment with TNFα-blockers reduced CD4 + CD28 null cells in most patients, only those carriers of the common GG genotype reached values within the range of HC and showed a disease activity improvement correlated to this decrease.Our results provide evidence for a genetic basis of the premature immunosenescence of RA patients and highlight its potential role in clinical outcome after TNFα blockade.