The prophylactic activity of intranasal human interferon-a2 (HuIFN-at2) against natural rhinovirus colds was determined in a randomized, double-blind, placebo-controlled trial. A total of 304 working adults selfadministered sprays of (107 IU/day) or a placebo once daily. During 22 days of treatment, 13 (8.5%) placebo recipients but no HuIFN-a2 recipiehts had respiratory illnesses documented secondary to rhinovirus infection (P = 0.0002). The occurrence of illness with symptoms of tracheobronchitis was lower ini HuIFN-a2 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-a2 recipients during weeks 2 and 3 of treatm'ent. Symptoms (obstruction, discomfort, blood-tinged nasal mucus) or signs (punctate bleeding sites, erosions, superficial ulcerations) of nasal irritation occurred in 40 HuIFN-ax2 recipients during week 3 (P < 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-eL2 was efficacious in preventing rhinovirus colds under natural conditions.The common cold is a major cause of morbidity and industrial absenteeism in the United States, afflicting adults an average of 2 to 4 arnd children an average of 6 to 8 times annually (2, 6). The antigenic heterogeneity of the causative viruses has prevented the development of a cold vaccine. For example, the most frequently isolated agent, the rhinovirus, has 89 identified serotypes and more that are recogniZed but presently unnumbered. Specific antiviral compounds have not yet been shown to have clinically useful prophylactic or therapeutic activity.Prevention of natural colds has not been achieved previously except by geographical isolation. However, experimental rhinovirus infections in susceptible volunteers have been prevented by intranasal administration of multiple daily doses of either leukocyte-derived human interferon (HuIFN) (3,13,14) or recombinant DNA-produced 15). A recent study has also shown that single daily intranasal doses of HuIFN-a2 gave protection against experimental rhinovirus colds in volunteers (9).The current randomized, placebo-controlled, double-blind study determined the prophylactic efficacy and tolerance of daily intranasal spraying with Virology. Nose and throat specimens were collected from subjects reporting upper respiratory illness, and the swabs were transported on wet ice in beef heart infusion broth containing 1% bovine serum albumin, vancomycin (20 ,ug/ml), gentamicin (50 ,xg/ml), amphotericin B (1 ,ug/ml) and sheep anti-HuIFN-o2 antibody (2,500 neutralizing units per ml) (8). The broth was inoculated in 0.2-ml portions onto duplicate monolayers of MRC-5 fibroblast, HEp-2, primary rhesus monkey kidney, and human embryonic kidney cells