To investigate the mechanism by which macrophage inflammatory protein-1α (MIP-1α) affects graft-versus-host disease (GVHD), the expression and function of MIP-1α in 2 murine models of GVHD were evaluated. In irradiated class I and class II disparate recipients, the expression of messenger RNA (mRNA) and protein for MIP-1α was significantly increased in GVHD target organs after transfer of allogeneic lymphocytes compared to syngeneic lymphocytes. When lymphocytes unable to make MIP-1α were transferred, there was a decrease in the production of MIP-1α in the liver, lung, and spleen of bm1 (B6.C-H2^bm1/By) and bm12 (B6.C-H2^bm12/KhEg) recipients compared to the transfer of wild-type splenocytes. At day 6 there was a 4-fold decrease in the number of transferred CD8⁺ T cells in the lung and approximately a 2-fold decrease in the number of CD8⁺ T cells in the liver and spleen in bm1 recipients after transfer of MIP-1α–deficient (MIP-1α^−/−) splenocytes compared to wild-type (MIP-1α^+/+) splenocytes. These differences persisted for 13 days after splenocyte transfer. In contrast, the number of donor CD4⁺ T cells found in the liver and lung was significantly increased after the transfer of MIP-1α^−/− compared to wild-type splenocytes in bm12 recipients from day 6 through day 10. Thus, the transfer of allogeneic T cells was associated with the enhanced expression of MIP-1α in both a class I and class II mismatch setting. However, the increased expression only led to enhanced recruitment of CD8⁺, but not CD4⁺, donor T cells. Production of MIP-1α by donor T cells is important in the occurrence of GVHD and functions in a tissue-dependent fashion.