OBJECTIVE Progestins represent the most widely used form of endocrine therapy in advanced or recurrent endometrial carcinoma. Based on encouraging response rates in breast cancer with high-dose megestrol acetate (MA) 800 mg/d, this phase II trial assessed response rates in patients with endometrial carcinoma treated with high-dose MA. METHODS Sixty-three patients with recurrent or advanced endometrial carcinoma were entered into this Gynecologic Oncology Group (GOG) study. Patients had either failed to respond to or were considered incurable with local therapy and had not received prior cytotoxic or hormonal therapy. MA 800 mg/d was administered orally in divided doses. Standard GOG toxicity criteria were used. RESULTS Of 63 patients entered, 58 were assessable for toxicity and 54 for response. Of 13 responders (24%), six (11%) had a complete and seven (13%) a partial response. Four of the responses lasted greater than 18 months. Twelve patients (22%) had stable disease. The response rate of patients with grade 1 or 2 lesions (11 of 30, 37%) was significantly higher (P = .02) than that of patients with more poorly differentiated tumors (two of 24, 8%). There was no difference in response rates comparing advanced versus recurrent disease, cell type, including papillary serous lesions, site of disease, prior radiation, age, or weight. The median progression-free survival (PFS) and overall survival intervals were 2.5 and 7.6 months, respectively. Grade 3 weight gain (> 20%) was seen in three patients and grade 3/4 hyperglycemia in three. Three deaths secondary to cardiovascular events were possibly related to therapy; diabetes was also a contributing factor in all three cases. CONCLUSIONS High-dose MA is active in endometrial carcinoma, but appears to have no advantage over lower-dose progestins.