Studies were performed in an attempt to define underlying mechanisms of resistance in mice infected with strains of bacteria or protozoa which confer on the animals resistance against phylogenetically unrelated organisms. The rates of clearance of an intravenously inoculated suspension of carbon particles in resistant and control animals were the same, suggesting that enhanced reticuloendothelial clearance was not involved. Attempts to transfer resistance by injection of “hyper-immune” serum were unsuccessful. In vitro monolayer cultures of peritoneal macrophages from resistant mice were protected against necrotization by bacterial and protozoal challenge when compared with monolayers from normal mice, and there appeared to be a more rapid killing of the intracellular organisms by macrophages from the resistant mice. These findings suggest that the macrophage plays a major role in the heterologous cross-resistance observed in these animals. Continued macrophage “activation” in Toxoplasma and Besnoitia-infected mice is probably due to the continued activity of these parasites during the entire life span of the host.