Analysis of the immune response of a panel of intra-I-region recombinant mouse strains to LDH-B and MOPC-173 demonstrated that B10.ASR7(H2as3) and (H2as4) failed to mount T-cell-proliferative responses to MOPC-173 and LDH-B, respectively. To localize the level of the immune response defect in the B10.BASR1 strain, B10.BASR1 macrophages were shown to be incapable of presenting LDH-B to immune responder B10.ASR7 T cells. These results were confirmed using alloreactivity-depleted and B10.ASR7×B10.BASR1)F1 immune T cells. Failure of these strains to respond was shown not to be the result of T cell suppression, because cyclophosphamide and anti-Lyt-2.2–plus–complement treatments did not restore responsiveness. Furthermore, B10.BASR1 macrophages were incapable of educating naive responder T cells in vitro to LDH-B—however, naive nonresponder B10.BASR1 T cells could be educated by responder macrophages to LDH-B in vitro. These results suggest that the failure of B10.BASR1 to respond to LDH-B reflects a defect at the macrophage–T cell interaction level, perhaps related to expression of unique I-A molecules created by intra-I-region recombinatorial events.