Increasing evidence suggests that neurohumoral manifestations of heart failure may lead to insulin resistance, predisposing patients with heart failure to the development of glucose intolerance or worsening of existing diabetes. Theoretically, insulin-sensitizing thiazolidinediones (TZDs) should be beneficial in this patient population. A 74-year-old man with well-compensated systolic dysfunction and longstanding type 2 diabetes mellitus treated with glyburide began therapy with rosiglitazone 4 mg/day, which was increased to 8 mg/day after 1 month. Two weeks later he was seen with a 5-kg weight gain, shortness of breath, bibasilar rales, +S3 gallop, and increased jugular venous distention. Twelve days later symptoms worsened, with pulmonary edema on chest radiograph, continued weight gain, and +4 pitting edema resistant to oral diuretics. The patient was admitted to the hospital for exacerbation of heart failure. Five days after discharge he was readmitted for similar symptoms, including an 11.8-kg weight gain. He reported adherence to drug therapy and diet. Rosiglitazone was immediately discontinued and 11 days later the man's weight stabilized to 79 kg and remained between 79 and 80 kg 2 and 3 months after discharge. This case demonstrates that TZDs may precipitate weight gain and pulmonary and peripheral edema in patients with stable heart failure. Earlier reports documented similar symptoms in patients without a history of heart failure. Although current recommendations state that TZDs should not be administered to patients with New York Heart Association class III or IV disease, practitioners should be aware that these adverse effects also may occur in patients with milder forms heart failure as well as those without heart failure.