The prophylactic activity of intranasal human interferon-alpha 2 (HuIFN-alpha 2) against natural rhinovirus colds was determined in a randomized, double-blind, placebo-controlled trial. A total of 304 working adults self-administered sprays of HuIFN-alpha 2 (10(7) IU/day) or a placebo once daily. During 22 days of treatment, 13 (8.5%) placebo recipients but no HuIFN-alpha 2 recipients had respiratory illnesses documented secondary to rhinovirus infection (P = 0.0002). The occurrence of illness with symptoms of tracheobronchitis was lower in HuIFN-alpha 2 recipients (one eposide) than in placebo recipients (eight episodes, P = 0.04). In contrast, the frequency of nasal symptoms and the overall rate of respiratory illness were significantly higher in HuIFN-alpha 2 recipients during weeks 2 and 3 of treatment. Symptoms (obstruction, discomfort, blood-tinged nasal mucus) or signs (punctate bleeding sites, erosions, superficial ulcerations) of nasal irritation occurred in 40 HuIFN-alpha 2 recipients during week 3 (P less than 0.0001 versus placebo recipients). Although the results of the current study were partially confounded by the nasal side effects of prolonged administration, they showed that intranasal HuIFN-alpha 2 was efficacious in preventing rhinovirus colds under natural conditions.