The influence of sodium lauryl sulfate (SLS) on the efficacies of gel formulations of foscarnet against herpes simplex virus type 1 (HSV-1) cutaneous lesions and on the establishment and reactivation of latent virus has been evaluated in a murine model of orofacial infection. Topical treatments were given twice daily for 3 days and were initiated at 6, 24, and 48 h after virus inoculation. The gel formulation that contained both 3% foscarnet and 5% SLS and that was administered within 48 h postinfection reduced the rate of development of herpetic skin lesions. This formulation also significantly decreased the viral content in skin tissues and in ipsilateral trigeminal ganglia when it was given within 24 and 6 h postinfection, respectively. A lower level of efficacy was observed for the gel formulation containing 3% foscarnet alone. Of prime interest, the gel formulation containing 5% SLS reduced significantly the mortality rate among mice in a zosteriform model of infection. Both formulations of foscarnet had no effect on the mean titers of reactivated virus in explant cultures of ipsilateral and contralateral trigeminal ganglia from latently infected mice. The use of a gel formulation containing combinations of foscarnet and SLS could represent an attractive approach for the treatment of herpetic mucocutaneous infections.