Six human immunodeficiency virus-infected patients had clinical lesions of herpes simplex virus (HSV) type 2 that showed in vitro resistance to foscarnet. In each patient, lesions were unresponsive to foscarnet therapy or developed during daily suppressive foscarnet. Five patients had a history of intermittent or chronic foscarnet use for the management of acyclovir-resistant HSV infection, and 1 was receiving daily foscarnet for suppression of cytomegalovirus retinitis. Seven of 10 foscarnet-resistant isolates from 6 patients were susceptible to acyclovir in vitro, and 1 was of borderline susceptibility. In 3 patients, the administration of acyclovir, either alone or in combination with foscarnet, resulted in healing. Clinically significant resistance to foscarnet may occur in immunosuppressed patients with prior foscarnet exposure. Addition or substitution of acyclovir to foscarnet therapy may be a useful strategy for patients in whom foscarnet resistance is suspected, pending the results of in vitro susceptibility testing.