Methotrexate is the most widely used second-line treatment in rheumatoid arthritis because of its excellent efficacy and safety profile. However, since 1991, about 100 cases of lymphoproliferative disorders have been reported in rheumatoid arthritis patients under methotrexate therapy. Four characteristics similar to those in lymphomas associated with immunodeficiency were identified during a review of the 48 cases for which detailed information is available. (1) Most cases were non-Hodgkin's B-cell lymphomas of the large cell or diffuse mixed type. (2) Extranodal involvement (55% of cases) was unusually common. (3) Evidence of Epstein-Barr infection was found in 46% of tested patients. (4) Of the 14 patients treated by methotrexate withdrawal alone, eight achieved a full remission, with follow-ups ranging from one to five years. These characteristics suggest a role for two factors: (1) the abnormalities in cell-mediated immunity seen in rheumatoid arthritis may promote latent Epstein-Barr virus infection, which may in turn lead to proliferation of malignant lymphoid cells; (2) the immunomodulatory effects of methotrexate may promote the development not only of opportunistic infections but also of Epstein-Barr virus-related lymphoproliferative disorders. There is no firm evidence to date that methotrexate has a direct oncogenic effect and no excess in malignant diseases has been reported with this drug. In conclusion, the rate of occurrence of lymphoproliferative disorders induced by low-dose methotrexate therapy remains controversial, although the characteristics of the malignancies and the possibility of a complete remission after methotrexate withdrawal militate against a chance association. Epidemiologic and other studies are needed to clarify this issue.