The numbers of Kupffer cells (macrophages) and pit cells (large granular lymphocytes) were counted by light and electron microscopy in perfusion-fixed liver sinusoids. After a single intravenous injection of the biological response modifiers zymosan, Propionibacterium acnes and OK-432, a 4- to 6-fold increase in the number of pit cells and a 2- to 4-fold increase in the number of Kupffer cells were observed within a period of 4 to 7 days. The mechanisms of the pit cell accumulation were further studied by the metaphase arrest method and by selective irradiation of the liver, or of the rest of the body, with a dose of 8.5 Gy. Stimulated pit cells showed mitotic activity in the liver and to a lesser extent in peripheral blood. The zymosan-induced increase in pit cell number was inhibited by irradiation of the liver but not by irradiation of the rest of the body (with shielded liver). It is concluded that the hepatic pit cell population, which has been shown to have natural tumoricidal activity, can be induced to expand by biological response modifiers, and local division of preexisting cells contributes significantly to this expansion.