In an attempt to find a dose of recombinant leukocyte A interferon (rIFN-alpha A) that is both efficacious against rhinovirus challenge and is tolerable, double-blind, placebo-controlled studies were performed; 56 normal volunteers received either placebo or one of two relatively small doses of rIFN-alpha A (i.e., 2.4 X 10(6) units [2.4M] or 0.7 X 10(6) units [0.7M] per day) for four days. The frequency of illness was significantly lower in the group given doses of 2.4M than in a group of volunteers given placebo (29% vs. 73%; P less than .032); however, the frequencies of illness in the group given doses of 0.7M and in a placebo group were similar (67% vs. 63%). The rates of infection in these pairs of groups were not significantly different from each other. No significant local or systemic reactions were noted during the four days of rIFN-alpha A administration. In a 26-day tolerance study, 15% of volunteers given 2.4M doses of rIFN-alpha A developed bloody mucus and nasal mucosal erosions, while no such local reactions were noted in volunteers given 0.7M doses or in those given placebo. Thus, increasing doses of rIFN-alpha A were associated with both increasing efficacy against rhinovirus-induced illness and increasing frequency of local adverse reactions.