Fludarabine is an important therapeutic option in patiens with chronic lymphocytic leukemia/diffuse small cell lymphoma. Adverse effects of fludarabine include myelosuppression, immunosuppression and autoimmune phenomena. We describe a case of symmetrical inflammatory seropositive polyarthritis consistent with rheumatoid arthritis in a patient with indolent non-Hodgkin's lymphoma who was being treated with fludarabine. A 67 year old Caucasian male was diagnosed with advanced stage mantle zone lymphoma in 1992. He was treated with six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and achieved a complete response. In 09/1996 he presented with progressive lymphadenopathy and pathology review resulted in a change in the histological diagnosis to diffuse small lymphocytic lymphoma. He was given two cycles of fludarabine 50 mg per day (25 mg/m2 IVdays 1-5, q28 days) with evidence of response. On day 23 of cycle two he complained of arthralgias involving his wrists, hands, shoulders, elbows and knees. Ibuprofen provided some relief. On day 4 of the third cycle the patient developed increasing symmetrical wrist, hand and knee pain and stiffness. Examination showed synovial thickening in MCP and PIP joints and marked effusions in both knees. Prednisone 25 mg daily was given with symptomatic improvement. Laboratory studies revealed a rheumatoid factor of 394 lU/mL (normal<80), anti-nuclear antibodies 5 (normal<5) in a homogeneous pattern and a low C4 complement level (<0.10 g/L). Radiographs showed no erosions in his hands and feet; there was mild narrowing of the medial joint space of the right knee. The patient was treated with non-steroidal anti-inflammatories, hydroxychloroquine (400 mg/ day) and the prednisone was eventually discontinued. No further fludarabine was given. Subsequent relapses of lymphoma were treated with chlorambucil in 1998 and CVP (cyclophosphamide, vincristine, prednisone) in 1999. The patient was last seen in June 2000 and had no significant joint complaints and his lymphoma was controlled. T lymphocytes play a role in the pathogenesis of rheumatoid arthritis. Fludarabine causes lymphopenia and lymphocyte dysfunction and has been used in uncontrolled studies to treat patients with rheumatoid arthritis. Fludarabine has been associated with the development or expression of underlying autoimmune disorders, particularly autoimmune hemolytic anemia; we believe this is the first report of a symmetrical inflammatory polyarthritis consistent with rheumatoid arthritis developing while on fludarabine. We encourage physicians to be aware of musculoskeletal symptoms in patients receiving fludarabine since they may represent autoimmune phenomena.