The case of a 25-year-old homosexual man with large inguinal and perianal ulcers is reported. He had been pretreated extensively with acyclovir. Herpes simplex virus (HSV) was identified in the ulcer tissue byin-situ hybridization. No clinical improvement with acyclovir but a prompt response to foscarnet was noted. In a relapse after 11 weeks an acyclovir-resistant HSV type 2 was isolated. Again, a prompt response to foscarnet was noted. The case is presented in detail, and the clinical impact of resistance of HSV to acyclovir is discussed.