Natural killer-like cellular cytotoxicity was augmented by incubation of human rhinovirus serotype 2 with peripheral blood mononuclear leukocytes collected from healthy donors. The production of alpha interferon but not gamma interferon was identified in the same cell cultures. A specific interaction of conformationally intact rhinovirus with peripheral blood mononuclear leukocytes was required for induction of the response, since the response was extinguished at reduced quantities of infectious rhinovirus, and acid inactivated rhinovirus did not augment cellular cytotoxicity. Productive replication of rhinovirus was not observed in cultures of peripheral blood mononuclear leukocytes. The replicative failure was not related merely to interferon production, since the rate of disappearance of rhinovirus was similar to that observed in cell free medium. The findings suggest that natural killer cells should be considered as a potential component of the local nasopharyngeal pathophysiology of rhinovirus infection.