Background: We attempted to originate a nonsurgical treatment alternative for cutaneous squamous cell carcinoma (SCC), and we evaluated intratumoral modified-release chemotherapy with fluorouracil/epinephrine injectable gel (5-FU/epi gel). Objective: To assess the safety and efficacy, we conducted an open-label pilot study of 5-FU/epi gel in 25 patients with biopsy-proven SCC lesions on the face, head, neck, trunk, arms, and hands. Methods: Each tumor site was injected intradermally with up to 1.0 ml of 5-FU/epi gel. One SCC per patient was treated weekly for up to 6 weeks, then observed for 4 months at which time the tumor site and margins were excised for histologic examination. Results: Overall, 96% (22 of 23) of evaluable treated tumors had histologically confirmed complete tumor clearing. No clinically significant systemic reactions or unexplained treatment-related adverse medical events occurred. The evaluations of the cosmetic appearance of the treated sites, judged subjectively by clinicians and patients, were mostly good to excellent and generally in close agreement. Conclusion: Treatment of superficial SCC with 5-FU/epi injectable gel results in a high rate of histologically confirmed complete tumor responses and may provide a nonsurgical treatment alternative in selected patients.(J Am Acad Dermatol 1998;38:438-42.)