Donor graft major histocompatibility complex class I antigens are targets for both allogeneic and xenogeneic rejection. Mice homozygous for beta 2-microglobulin gene disruption express reduced amounts of surface MHC class I antigens. Liver cells from such mutant mice were transplanted into isogeneic, allogeneic, and xenogeneic recipients to evaluate the potential of these animals as transplant donors. The survival of allografts of transgenic 129 mouse liver cells in 15 immunocompetent and histoincompatible mouse recipients (BALB/c, D1.C) was only slightly improved 30 days after transplantation relative to normal 129 mouse allografts. These results could be attributable: (1) to host natural killer cell-mediated lysis of donor MHC class I antigen-deficient cells; (2) to donor liver cell MHC class I determinants that are reduced but not eliminated serving as rejection targets; (3) to the plentiful host supply of serum beta 2-microglobulin reconstituting the graft and restoring donor MHC class I. Culture studies confirmed the ability of exogenous human and bovine beta 2-microglobulin to restore rapidly MHC class I antigen expression on transgenic cells. Because cell surface exchange of beta 2-microglobulin is less efficient between species with divergent beta 2-microglobulin sequences, the survival of transgenic 129 mouse liver cells in guinea pig (60% beta 2-microglobulin identity) and Xenopus (34% beta 2-microglobulin identity) hosts was investigated. Significant prolongation of MHC class I antigen-deficient liver cell xenografts was apparently only in Xenopus hosts. Furthermore, transplants of transgenic 129 mouse liver cells into isogeneic normal 129 mouse recipients showed evidence of rejection in seven of nine recipients, suggesting that transgenic donor cells also may be susceptible to lysis by host natural killer cells.