Inactivation of varicella zoster virus in vitro by nonadherent, mononuclear peripheral blood leukocytes and antibody is described. When leukocytes and specific antibody were incubated with this virus, marked inactivation of the virus occurred. In contrast, leukocytes alone or with serum devoid of varicella zoster antibody caused only a small degree of inactivation of varicella zoster virus. The leukocytes involved appeared not to be monocyte-macrophages or T or B lymphocytes, and only minute amounts of specific antibody were required. We had found previously that leukocytes from unsensitized (varicella susceptible) as well as sensitized (varicella immune) donors could cause this reaction. We therefore propose that the reaction may be a form of antibody-dependent cellular cytotoxicity, as has been described for 51Cr release by lymphoid (K) cells for other herpesviruses.