Wasting protein-energy malnutrition (PEM) was induced in male C57BL/6J mice fed a low-protein diet ad libitum from 23 to 37 d of age. In comparison with a complete diet, the low-protein formulation reduced delayed hypersensitivity to sheep red blood cells (SRBCs) assessed on day 14 of feeding by measuring increased footpad thickness (mean +/- SD: 4 +/- 4% vs 22 +/- 8%, P less than 0.01), after immunization on day 9, and after challenge with SRBCs on day 13. By contrast, the low-protein diet did not affect the anti-SRBC hemagglutinin titer (8.3 +/- 2.2 vs 9.1 +/- 1.1, P greater than 0.30) despite profound reduction in numbers of splenic plasma cells secreting IgM-class anti-SRBCs (7.3 +/- 3.1 vs 49.9 +/- 23.8 x 10(-3), P less than 0.001), after immunization on day 9 and assessment on day 14. Thus, direct experimental evidence, previously altogether lacking, is provided in support of the concept, central to nutritional immunology, that acquired cell-mediated immunity is less resistant than is systemic humoral immunity to the depressive influence of pre-adolescent, wasting PEM.