The cerebral neocortex is known to modulate asymmetrically certain components of the immune system. It was previously shown that large ablation of the left cortex reduces B and T cell-mediated responses, whereas symmetrical right lesions enhance these responses. We have studied the immunomodulatory role of the brain cortex on the mononuclear phagocytic system. Resident and BCG-activated macrophages were investigated in female C3H/He mice at 8-10 weeks after right or left cortical ablation. After an intraperitoneal injection of BCG, the number of peritoneal macrophages was found to be lower in both right- and left-lesioned mice, the difference being stronger and more significant in left-lesioned animals than in sham-operated controls. Furthermore, the oxidative metabolism as assessed by chemiluminescence was depressed only in left-lesioned mice. On the other hand, cortical lesions were shown to have no effect on either the number or the endocytic activity of resident peritoneal macrophages. The possible implication of the brain neocortex on infectious diseases was assayed by using the Trypasonoma musculi model, in which macrophages are known to be effective in parasite eradication. Although the number of peritoneal macrophages was significantly depressed after left cortical lesions 11 days after T. musculi inoculation, the course of the infection was not modified significantly. Our results argue in favor of brain neocortex modulation of the mononuclear system.