OBJECTIVE To report a case of severe prolonged thrombocytopenia possibly associated with isotretinoin. METHODS A 27-year-old white woman developed severe thrombocytopenia and elevated transaminases after 3(1/2) months of treatment with isotretinoin. Prior to the onset of thrombocytopenia, the patient had also received a 10-day course of cephalexin. Rectal bleeding was reported by the patient, who was otherwise asymptomatic. Liver enzyme values returned to normal approximately 1 week after discontinuation of isotretinoin; however, platelet counts required approximately 2 months to normalize. Based on the Naranjo probability scale, possible causality exists between isotretinoin and thrombocytopenia. CONCLUSIONS The exact mechanism by which isotretinoin caused thrombocytopenia in this patient is not clearly understood. To our knowledge, only 3 previous cases of isotretinoin-associated thrombocytopenia have been reported. The long recovery process that occurred in our patient is possibly a direct result of the long elimination half-life of both the parent compound and active metabolites of isotretinoin. CONCLUSIONS Clinicians prescribing isotretinoin should be aware of the potential life-threatening consequence of thrombocytopenia, and a complete blood cell count with platelets should be part of the routine monthly monitoring in all patients receiving isotretinoin therapy.