Mice immunized subcutaneously in the footpad with P40, an insoluble fraction extracted from delipidated heat-killed Corynebacterium granulosum, developed systemic mechanisms which depended on the generation of a state of systemic cellular hypersensitivity to P40 antigens. An injection of P40 into the footpad resulted in a striking increase in cell division in the draining lymph node, the development of a state of specific systemic delayed type hypersensitivity and a systemic increase in the bacterial capacity of the host macrophages. The footpad containing the immunizing injection of P40 also reflected the generation and decay of host sensitivity. Whereas the expression of 24-h skin sensitivity reactions to the eliciting injection of P40 antigens peaked at about day 6, the maximal increase of the local granuloma reaction peaked at about day 14, the latter representing a cumulative reaction. These local reactions and systemic hypersensitivity did not develop in congenitally athymic Nude mice. Time- and dose-dependent variations were detected in different strains of mice. Systemic hypersensitivity could be transferred to normal recipients with lymph node cells or spleen cells but not with serum from P40-immunized donors. All the results produced in this report indicate the distinct possibility that the systemic hypersensitivity which developed after P40 sensitization was based on cell-mediated responses to P40 antigens.