The efficacy of 5% acyclovir in a modified aqueous cream vehicle (ACV-MAC) in the treatment of recurrent herpes labialis was tested in a randomized, double-blind clinical trial with the modified aqueous cream vehicle as a control medication. The ACV-MAC formulation has previously been shown to offer superior cutaneous absorption relative to other topical acyclovir formulations. Treatment was initiated by patients within 1 hour of prodrome in an attempt to maximize clinical impact of this virustatic drug. While the patient group receiving active drug showed a trend toward accelerated healing, no significant differences for lesion or healing characteristics could be measured between the two treatment groups. It is suggested that optimal efficacy of ACV-MAC may be predicated on prophylactic treatment, that is, "trigger"-initiated rather than prodrome-initiated treatment.