Methotrexate (MTX) is an antiproliferative agent that is used in the treatment of patients with rheumatoid arthritis (RA). It can cause pancytopenia, which is observed rarely but can be fatal. In this article, we present three RA cases on MTX with multiple risk factors and comorbid diseases who developed MTX toxicity and pancytopenia. We suggest that there should be risk classifications for RA patients who are candidates for MTX treatment. Patients with multiple risk factors, those with poor cooperation who might have problems in receiving medication, and those who do not seem to follow regular visits might be better started on another disease-modifying agent.