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Thrombocytopenia is an uncommon side effect of trimethoprim/sulfamethoxazole (TMP/SMX) when given in the usual recommended adult dosage. We report a case of severe and possibly life-threatening thrombocytopenia associated with TMP/SMX therapy. A 92-year-old female presented after a mechanical fall and subsequent intractable bleeding from a laceration on her left leg. She had a history of cellulitis of the lower extremities treated with a 10-day course of TMP/SMX. Her last dose was two days before the visit. The physical examination was significant for a small laceration on her left shin, with persistent oozing of blood. Her blood work was notable for white blood cells (WBC) 9.4×10^9/L (9.4×10^3/mm^3), hemoglobin 125g/L (12.5 g/dL) and platelets 5×10^9/L (5×10^3/mm^3). A repeat platelet count was 4×10^9/L. Prothrombin time was 11 seconds and the international normalized ratio (INR) was one. The TMP/SMX was discontinued and one unit of platelets was transfused. Her platelet count subsequently increased to 108×10^9/L. Severe thrombocytopenia with a platelet count of ≤10×10^9/Lmay rarely result in the catastrophic spontaneous bleeding. Thus, low platelet counts associated with TMP/SMX carry potential life-threatening complications. The clinicians should be aware of this adverse effect of TMP/SMX, which appears to be dose/duration independent. We suggest careful monitoring of complete blood cell count, especially platelet count, before and during TMP/SMX therapy.