The genetic control of contact photosensitivity (CPS) to 3,3',4',5-tetrachlorosalicylanilide (TCSA) was studied in H-2- and IgH-congenic mice. The H-2 complex was found to play a major role in determining the pattern of responsiveness, whereas the effect of the Igh locus on the response was not apparent. The H-2k haplotype was closely associated with low responders, whereas mice with the H-2b,d alleles were high responders. The responsiveness of the H-2k strains was converted from low to high levels by treatment with cyclophosphamide (CY) before photosensitization. Transfer of spleen cells from photosensitized H-2k mice showed a suppressive effect on the development of the CPS reaction of syngeneic recipients pretreated with CY. These spleen cells contained antigen-specific CD4+, CD8- suppressor T cells (Ts) that functioned in the induction phase of CPS. The in vitro proliferation of immune lymph node T cells pulsed with photohapten-coupled cells plus peritoneal adherent cells was suppressed by the addition of anti-I-A monoclonal antibody in both H-2d and H-2k strains, suggesting that the I-A molecule are responsible for inducing the positive immune response. On the other hand, such proliferation was significantly enhanced by the addition of anti-I-E alpha antibody in H-2k, but not H-2d, mice. This implies that the low responsiveness of CPS in the H-2k strain is due to the preferential activation of Ts via I-Ek molecules. The present observation further supports the important role of the I-E molecule in the suppressor circuit of CPS to TCSA.