The antimitotic drug vinblastine (Vbl) has a profound impact upon the specifically sensitized lymphocytes that transfer cellular resistance to Listeria monocytogenes. A 12-h pulse of the drug given to prospective donors during the first week of an immunizing Listeria infection inhibits the delivery of protective lymphocytes to the thoracic duct and their subsequent movement into an inflammatory exudate induced in the peritoneal cavity. The effect of Vbl is clearly related to its antimitotic activity, not to an effect on lymphocytes regardless of their position in the division cycle. This conclusion was drawn from an autoradiographic analysis of cells in the lymph of Vbl-treated rats and from failure of the drug to abrogate a known function of small lymphocytes, namely, their ability to initiate a graft-vs.-host reaction. The results imply that large lymphocytes, the rapidly proliferating cells in central lymph, are the principal effector cells responsible for transmitting resistance to L. monocytogenes and provide a plausible explanation for their rapid turnover and short circulating life-span.