The aim of this double-blind, placebo-controlled, comparative study was to differentiate the clinical efficacy and tolerability of human leukocyte interferon-alpha incorporated (2 x 10(6) IU/g) in a hydrophilic cream and in a gel to heal males afflicted with first episodes of genital herpes. Patients (n = 60), aged 18-40 years (mean 23.2) with culture-confirmed diagnosis of herpes genitalis were randomized to three parallel groups. Each patient was allocated a precoded 40-g tube, containing either preparation or placebo. Cream or gel was applied three times daily for 5 consecutive days. The duration of the active treatment was two weeks. Patients were examined after 48 hours in initial treatment, and thereafter two times a week. A reepithelialized lesion with some residual erythema was recorded as healed. The study demonstrated that patients treated with leukocyte interferon-alpha cream had both significantly shorter mean duration of lesions than gel and placebo recipients (5.3 days vs. 8 days, 13 days respectively; p < 0.001) and a higher number of healed patients (80% vs. 55%, 20% respectively; p < 0.001). Of the 60 patients, 49 (82%) complained of no drug-related side effects. Eleven patients predominantly in the cream/gel groups reported non-objective transitory increase in their body temperature (> 38 degrees C) with moderate headache, malaise and myalgia. The study was followed-up for 24 months after the first day of the treatment, and out of 31/60 cured patients, 4 had a relapse after 18 months. In conclusion the study affirmed that human leukocyte interferon-alpha (2 x 10(6) IU/g) in a hydrophilic cream is more efficacious than its incorporation in gel or placebo, thus suggesting that leukocyte interferon-alpha in a hydrophilic cream, with a profile of non-objective mild to moderate drug-induced indications, may be considered an alternative and effective treatment modality to cure male patients afflicted with first episodes of genital herpes.