Hydatidiform Mole (H. mole) is an abnormal placenta subdivided into complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM). Management of H. mole includes laboratory examinations, molar evacuation, and recognition, recognition and treatment of medical complications. Identification of women at risk for malignant degeneration is also important in order to initiate prophylactic chemotherapy using Methotrexate or Actinomycin. Methotrexate, which is the preferred drug, is an antimetabolite that has a narrow therapeutic index and widespread clinical indications. Dose of Methotrexate given for 5 consecutive days as prophylactic chemotherapy resulted in severe toxicity in a young primigravid patient with complete hydatidiform mole. Conclusion: It is especially important for physicians to be cognizant of a possible adverse drug reaction in response to methotrexate.