Chronic inflammatory syndromes such as rheumatoid arthritis (RA) are associated with high frequencies of CD4+CD28- T cells. The number of these cells is genetically determined and may also be a consequence of chronic exposure to tumor necrosis factor-alpha (TNFalpha). The aim of this study was to examine whether the reported efficacy of anti-TNFalpha therapy in RA involves a resurgence of T cell populations that re-express CD28. After 36-week therapy with infliximab, a significant decrease in CD4+CD28- T cells in RA patients was observed in comparison with baseline. The results suggest that TNFalpha-neutralizing therapy may restore T cell homeostasis and reduce expansion of the CD28- T cells, which are cytotoxic and may contribute to organ manifestations in RA.