Background: In the past, radical margins of excision were prescribed for cutaneous melanoma based on preconceived notions rather than on hard clinical evidence. Methods: In a prospective study of 742 patients with intermediate-thickness melanoma (1-4 mm), 470 patients with trunk or proximal extremity lesions were randomized into a 2-or 4-cm margin. Patients with distal extremity or head and neck lesions (n = 272) received uniformly a 2-cm margin. Results: The overall rate of local recurrence was 3.8%. This rate in the randomized portion (n = 470) was 2.1% for the 2-cm margin and 2.6% for the 4-cm margin (p = 0.72). A progressive increase in local recurrence rates was observed with thickness: 2.3% for lesions 1.0-2.0 mm, 4.2% for those 2.01-3.0 mm, and 11.7% for those 3.01-4.0 mm thick (p = 0.001). Local recurrence occurred in 1.5% of those without ulceration and in 10.6% of those with ulceration of the primary lesion (p = 0.001). The local recurrence rate was not significantly affected by the margin of resection even among the thicker or ulcerated lesions. It also was not affected significantly by the method of closure of the primary site or management of the regional nodes, or the age or gender of the patients. Conclusions: A 2-cm margin is as effective as a 4-cm margin in local control and survival of intermediate-thickness melanomas. The local recurrence rate is significantly affected by the thickness of the primary lesion and the presence or not of ulceration. © 1996 The Society of Surgical Oncology, Inc.