Spleen cells from mice immunizied to produce a potent humoral response do not express delayed-type hypersensitivity (DTH). These cells, when cultured at low density in the presence of the specific antigen for about 6 days, are able to produce swelling of the footpads of normal mice 24 h after they are injected s.c. into the footpad with the appropriate antigen. This footpad swelling peaks 24-48 h after the injection of the cells, requires the presence of Ly-1+Ly-2- T cells in the immune population, is due to the interaction of antigen-specific cells with the appropriate antigen and is therefore due to DTH-mediating cells. The optimal generation of these cells occurs under conditions similar to those favoring the primary induction of DTH. Furthermore, the in vitro generated cells are also able to produce a systemic state of DTH when injected i.v.; a DTH reaction is elicited in recipient mice when antigen alone is injected into their footpads. The observations reported here demonstrate that a humorally immune population of spleen cells, known to contain T cells able to suppress the induction of DTH, can under appropriate conditions give rise to cells expressing this subclass of cell-mediated immunity. The decision by the immune system to mount a humoral as opposed to a cell-mediated response is therefore reversible. These findings provide grounds for believing that it should be possible to develop the means to switch an on-going in vivo humoral response to a cell-mediated one, a maneuver that would be of considerable benefit in some well-recognized clinical situations.