Keratoacanthoma is a common, benign cutaneous neoplasm that displays rapid growth on sun-exposed skin. Keratoacanthomas usually involute spontaneously after several months but rarely progress to squamous cell carcinoma. Because this is a benign, self-limited lesion of exposed skin, effective treatment should emphasize patient comfort and cosmetic results in addition to effectiveness. The authors present 2 patients with keratoacanthomas treated with topical 5-fluorouracil. Both patients had complete resolution of their lesions within 8 weeks. The cosmetic result was superb in both patients. Patient satisfaction with this therapy was excellent. Treatment can be instituted based on a clinical diagnosis; no diagnostic biopsy is necessary. Most keratoacanthomas respond to topical 5-fluorouracil therapy within 3 weeks, whereas squamous cell carcinomas respond poorly. Any lesion that shows a poor response after 3 weeks of therapy or that does not resolve within 8 weeks should undergo prompt excisional biopsy for definitive diagnosis and treatment. Topical 5-fluorouracil is an effective, convenient, relatively inexpensive treatment for keratoacanthoma that produces excellent cosmetic results. It should be added to the therapeutic armamentarium of all physicians who treat keratoacanthoma.