We conducted a randomized, placebo-controlled, double-blind study to determine whether intranasal alpha 2-interferon could prevent respiratory illnesses in healthy contacts of ill family members. Beginning within 48 hours of the onset of illness in a family member, contacts self-administered interferon (5 X 10(6) IU) or placebo spray once daily for seven days. Respiratory illness developed during the eight-day period, starting with the second day of spraying, in 52 of 222 persons in the placebo group as compared with 32 of 226 in the interferon group (P = 0.02; efficacy, 39 percent). Among persons exposed to laboratory-documented rhinovirus colds, illness developed in 2 of 27 interferon recipients as compared with 12 of 34 placebo recipients (P = 0.02; efficacy, 79 percent). During the two-week period during and after spraying, rhinovirus colds developed in 1.3 percent of those spraying with interferon and in 15.1 percent of those spraying with placebo (P = 0.003; efficacy, 88 percent). Blood-tinged mucus or nasal mucosal bleeding or both were detected in 7.7 percent of placebo and 13.6 percent of interferon users (P = 0.04), but no evidence of cumulative nasal toxicity was found. We conclude that postexposure prophylaxis with intranasal interferon may in some cases provide an effective strategy for controlling the spread of natural colds, especially those caused by rhinoviruses.