Arildone is an aryl diketone which is inhibitory in vitro against herpes simplex virus type 2 at a concentration of 2 ,ig/mi or less. One hundred forty-five patients with recurrent genital herpes were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial to evaluate the efficacy and safety of an 8% arildone cream. Patients initiated therapy a mean of 9.9 h and a maximum of 24 h after the reported onset of lesions and applied medication 6 times daily for 7 days. The duration of viral shedding was shorter among women (P < 0.05) and the duration of local itching was shorter among men (P < 0.05) in patients that received arildone than in those that received placebo, but there were no significant differences between treatment groups in duration of pain, time to crusting or healing of lesions, or percentage of patients developing new lesions. Mild local irritation after application of ointment was common and occurred equally in both treatment groups. Despite early application, topical arildone cream was ineffective in the therapy of acute recurrences of genital herpes.Recurrent genital herpes is a common sexually transmitted disease; 80 to 90% (4) of the estimated 300,000 patients (1,3) who experience first episodes of disease in the United States per year will have subsequent recurrences at a mean rate of four to five per year (4). Oral acyclovir, a recently licensed antiviral agent which acts by inhibiting viral DNA polymerase (6), shortens the duration of recurrent episodes of genital herpes (15) and, when used on a daily basis, can suppress recurrences altogether (5, 13, 17). There are concerns, however, over the potential for toxicity of a frequently used, systemically active DNA inhibitor and over the possibility of emergence of acyclovir-resistant herpes simplex virus (HSV) (7,17,19). Arildone (WIN 38020), an aryl diketone compound with broad-spectrum in vitro activity against a variety of RNA and DNA viruses (8,18), including HSV (10), appears to have a unique mechanism of antiviral action. It inhibits replication of poliovirus at an early step by preventing virion uncoating (12), and it has been found to protect against poliovirus-induced disease in mice (11). Its activity against HSV, although less well defined, also occurs early postinfection and prevents synthesis of both viral DNA and proteins (10). Furthermore, arildone is reported to be equally effective in vitro against both acyclovir-sensitive and acyclovir-resistant isolates (A. S.