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Recently, it has been shown that patients with rheumatologic diseases who are treated with methotrexate can develop immunosuppression-associated lymphoproliferative disorders. Although a variety of lymphoproliferations have been described in the setting of methotrexate therapy, only rare cases of Hodgkin's disease (HD) have been reported. In this study, we provide a more complete characterization of the spectrum of lymphoproliferations that resemble HD or show features diagnostic of HD that occur in patients receiving long-term low-dose methotrexate therapy. Eight patients were receiving methotrexate for various disorders. Four cases were considered to represent lymphoproliferations resembling HD; the other four cases were diagnosed as HD because they showed diagnostic morphologic and immunophenotypic features. All three patients with lymphoproliferations resembling HD on whom follow-up was available experienced tumor regression with methotrexate withdrawal or with methotrexate withdrawal and steroids; none of these three patients required further therapy. All three patients with HD on whom follow-up was available are alive and free of disease following chemotherapy or radiation therapy. In two of these patients, the tumor persisted or progressed despite discontinuation of methotrexate with observation; the third patient received chemotherapy at the same time methotrexate was stopped. Our findings indicate that a spectrum of lymphoproliferations resembling HD or diagnostic of HD can occur in patients receiving long-term low-dose methotrexate therapy. Recognition of these lymphoproliferative disorders is clinically important because a subset of these neoplasms will completely resolve with discontinuation of methotrexate, thereby obviating the need for chemotherapy or radiation therapy.