B10.A animals were rendered tolerant to B10.M spleen cells by injection of (B10.A X B10.M)F1 cells into neonates. Adult animals accepted B10.M skin grafts and failed to generate cytotoxic effector cells in vitro against B10.M H-2 antigens. In vivo inoculation of tolerant animals with A.CA spleen cells, followed by in vitro challenge with similar cells, resulted in the generation of cytotoxic effector cells that had specificity for the A strain minor histocompatibility (H)-antigens in the context of the H-2f haplotype. If these animals were boosted in vitro with A strain spleen cells, cross-priming could be demonstrated, whereby the cytotoxic effect was restricted by the H-2a haplotype. These data indicate that at least two sets of T cells co-exist in tolerant animals, one capable of recognizing antigens in the context of the host H-2 haplotype, and the other able to recognize antigens in the context of the tolerated H-2-allogeneic haplotype. Because tolerant animals inoculated with A-strain spleen cells in vivo and boosted in vitro with A.CA spleen cells failed to generate a cytotoxic effect against A.CA, it is unlikely that minor H-antigens need to be processed by host lymphoreticular cells.