Clinical experience demonstrates that oral acyclovir (ACV) is superior to topical ACV in treating recurrent cutaneous herpes simplex virus type 1 (HSV-1) infections. Cutaneous HSV-1 infections are complex in their pathology, affecting the basal epidermis in skin as well as establishing a latency phase in sensory ganglia. In vitro and in vivo human skin model systems were used in the present study to quantitate ACV disposition and absorption in skin and blood following two routes of administration and to investigate whether bioavailability differences were the result of insufficient drug delivery. Physiochemical and physiologic parameters determined from these experiments were used to develop a mathematical model to predict ACV disposition and absorption in human subjects. Model predictions and in vivo data agree; topical administration of commercial 5% ACV ointment and cream result in a 48 times greater total epidermal ACV concentration than after oral administration. Mathematical modeling of the ACV concentration gradient through the epidermis revealed, however, that the drug concentration in the target site of HSV-1 infections, the basal epidermis, is 2-3 times less after topical administration than after oral administration. Thus, the observed lack of clinical efficacy with topical ACV therapy in the recurring HSV-1 infection likely reflects the insufficient delivery of the drug to the target site of the HSV-1 infection, the basal epidermis.