Methotrexate is used judiciously, only when specifically indicated. However, in this case the patient had a fatal outcome after only three doses. A young nulliparous woman diagnosed as having high-risk persistent trophoblastic disease was considered for multidrug chemotherapy. However, because of persistent low-grade fever it was decided to give only single agent, methotrexate. She developed severe toxicity which proved fatal, even before the first course could be completed. Analysing causes of this rare, unexpected outcome of methotrexate administration, suggested that estimation of serum levels can be a useful tool in monitoring patients showing hypersensitivity but this facility is rarely available especially in low-resource countries. Pharmacogenetical analysis of blood/tissue sample may be useful to help in identifying patients likely to show hypersensitivity reaction.