We studied the effect of a 6-month treatment with low-dose MTX in 22 RA patients, with the purpose of investigating the relationship of sIL-2R and IL-6 serum changes with those of class specific RFs. The patients with RA had higher serum levels of sIL-2R (p < 0.0001), and IL-6 (p < 0.0005) than healthy volunteers. We found that the levels of IgM-RF (p < 0.0004), IgA-RF (p < 0.002), IgG-RF (p < 0.025), sIL-2R (p < 0.017) and IL-6 (p < 0.044) as well as the main clinical and laboratory variables, were significantly reduced in RA patients treated with low dose MTX for six months. The changes from baseline of IgM-RF correlated with those of IL-6 (p < 0.023), suggesting that MTX may affect IL-6 and IgM-RF production in part by a common mechanism. In conclusion our results show that there is a relationship between IL-6 and IgM-RF changes from baseline during MTX therapy, but the hypothesis of a link between the effects of this drug on cytokine network and RF production needs further investigation.