The first evaluation of intranasal (i.n.) recombinant human interferon-gamma (rHuIFN-gamma) as prophylaxis against experimental rhinovirus (RV) infection and illness in volunteers is reported. In two studies, 7 of 27 (26%) of the volunteers who received rHuIFN-gamma (2 Mu i.n. 3 x /day) had either blood stained nasal secretions or nose bleeding which was not observed in any of the 26 placebo recipients. Some volunteers given rHuIFN-gamma showed increased nasal secretion and the majority complained of slight nasal stuffiness, whereas only a few of those receiving placebo complained of these symptoms. In the prophylactic study, 17 volunteers were given the above regimen of rHuIFN-gamma and 17 placebo; after the fourth dose all were challenged with RV9, followed 1 h later with RV14 (100 TCID50 of each virus). Compared with the placebo-treated controls, interferon recipients showed no significant reduction in the proportion who developed colds or became infected, and there was an increase in both their mean clinical scores and mean nasal secretion weights. Thus i.n. rHuIFN-gamma did not prevent rhinovirus infection or illness and may enhance the symptoms.