Spleen weights and mitogen responsiveness of splenocyte cultures from scrapie agent-infected and control-inoculated mice were compared over two-month periods following inoculation. Splenocytes from Swiss, C57B1, and BALB/c mice were stimulated with the T (thymus-derived) cell mitogens phytohemagglutinin or concanavalin A, the B (bone marrow-derived) cell mitogen bacterial lipopolysaccharide, or pokeweed mitogen, a stimulator of both T and B cells. Although significant splenomegaly was associated with scrapie infection, we failed to observe any significant differences in the activation of experimental and control cells. Studies with BALB/c mice suggested the possibility, however, that with both phytohemagglutinin and lipopolysaccharide, specific decreases in lymphocyte activation might occur with more optimal culture conditions. The data are consistent with the idea that the scrapie agent stimulates only subtle immunological changes within the host as it destroys the cells of the central nervous system.