Methotrexate (MTX) is one of the most widely used antirheumatic drugs for the treatment of rheumatoid arthritis. Whereas the hepatotoxicity of methotrexate is well recognized, the hematologic toxicity, namely, pancytopenia, is still a concern and is potentially fatal. We report two cases of early-onset methotrexate-induced pancytopenia that were successfully treated with granulocyte colony-stimulating factor (G-CSF). The pancytopenia improved with 3 days of administration. A review of the literature revealed at least 146 reported cases of MTX-induced pancytopenia. Significant risk factors for myelotoxicity included renal impairment, infection, and hypoalbuminemia. Successful management includes prompt discontinuation of MTX, intravenous folinic acid, high-dose steroids and, as in our case, G-CSF.