Rhinovirus type 15 passaged three times in WI-38 cells produced illness in only one of 35 volunteers, but infection resulted in formation of significant quantities of antibodies in the serums of 100%, and in nasal secretions of 89%, of infected volunteers. The inoculum contained large- (60%) and small- (40%) plaque variants. "Purified" large- and small-plaque inocula were prepared, and each was administered to 20 volunteers. There was a significant association of illness with the small-plaque inocula (P < 0.01) but the incidence of infection, quantitative virus shedding patterns, and mean serum and nasal secretory antibodies were not significantly different between the two groups. These findings suggest that plaque size may be an in vitro marker of attenuation of illness production by rhinoviruses.