The prophylactic effect of low doses of human leukocyte interferon (HuIFN-alpha) against infection with rhinovirus was measured in double-blind, placebo-controlled studies with volunteer subjects. An antihistamine (chlorpheniramine) was given before administration of single or multiple doses of HuIFN-alpha but saturated cotton pledget or by aerosol; volunteers were then challenged with rhinovirus. When the results for all groups were combined, a lower frequency of respiratory illness was demonstrated in the HuIFN-alpha-treated volunteers (20 of 39 vs. 11 of 38, P less than 0.05). A significant improvement in mean symptom scores was found only in the volunteers who received HuIFN-alpha by cotton pledget. The total numbers of isolates of rhinovirus and seroconversions were similar for HuIFN-alpha-treated and control volunteers. No significant side effects were noted in the HuIFN-alpha-treated volunteers. Higher concentrations or improved methods of delivery of HuIFN-alpha will be necessary for improving the clinical efficacy of HuIFN-alpha against viral infections in the respiratory system.