We compared the effects of MTX alone and MTX plus 4-hydroperoxycyclophosphamide (4-HC), an active metabolite of CTX in vitro, on the expression of P-gp and investigated the involvement of the JAK2/STAT3 pathway to clarify the mechanisms underlying the MXT + 4-HC-induced modulation of P-gp expression in RA fibroblast-like synoviocytes (FLSs). This evidence concerns the gene STAT3 and rheumatoid arthritis.