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We are going to alert the emergency physicians to be aware of drugs side effects. Some drugs like methotrexate are not routine drugs, and the symptoms may be miss diagnosed if not completely notified. Case Presentation: We present two patients under treatment with methotrexate. Both of them suffered from methotrexate poisoning due to improper use. We discuss the causes of methotrexate poisoning and its prevention. Conclusion: A significant proportion of methotrexate users may not be completely aware of its proper use and the side effects. One of the important ways to prevent the toxicity of methotrexate is educating patients and their companions in order to use it correctly.