Previously, we have shown that the intravenous (i.v.) injection of allogeneic lymphocytes across an H‐2 class I‐mutant disparity leads to specific skin allograft tolerance caused by irradiation‐sensitive donor T cells, which function as veto cells. In the present study, we show that the i.v. injection of H‐2 class II‐incompatible spleen cells also results in specific skin allograft tolerance. However, tolerance induction depends on the presence of irradiation‐resistant non‐T cells in the donor cell inoculum. Thus, different mechanisms operate in tolerance induction across an H‐2 class I vs. H‐2 class II mismatch. I.v. injection of allogeneic spleen cells across an H‐2 class I plus class II disparity does not result in skin allograft tolerance. Finally, our data show that transfusion‐induced suppression of the delayed‐type hypersensitivity response against alloantigens does not correlate with skin allograft tolerance induced by i.v. injected allogeneic lymphocytes. In conclusion, the type of H‐2 mismatch between transfusion donor and recipient not only determines the occurrence of allograft tolerance but also the mechanism leading to tolerization. Copyright © 1990 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim