We studied the in vitro and in vivo cellular response in three distinctly different xenograft models, using C57BL/6 mice as responders and Lewis rats (LR), Golden Syrian hamsters (GSH), and Strain 2 guinea pigs (GP) as stimulators. Previous work has shown that cardiac grafts from rats, hamsters, and guinea pigs are rejected by C57BL/6 mice in 7 days, 4 days, and 10 min., respectively. In xenogeneic mixed lymphocyte culture, response was in general greatest to GSH splenocytes: stimulation index (S.I.) = 11.4 ± 3.6 followed by the response to LR cells, S.I. = 3.5 ± .09, which was less than that of an allogeneic control C57BL/6 anti-DBA, S.I. = 8.4 ± 1.7. GP stimulator splenocytes produced inhibition of response (S.I. = 0.23 ± .07) with all counts being below baseline and remaining low despite addition of IL-1, IL-2, or both. In fact, these cells were inhibitory to other allo or xeno mixed lymphocyte cultures in a dose-dependent manner. Cytotoxicity studies revealed maximal killing of ConA blasts in the allogeneic control followed by killing of GSH blasts and LR blasts and no killing of GP blasts. There was also a moderate degree of nonspecific killing between allo and xeno systems. In vivo analysis of cell-mediated cytotoxicity was done using a sponge matrix allograft model. The sponge was injected with donor cells and implanted into C57BL/6 mice. The response to donor cells was tested using cells accumulating in the sponge. There was maximal response to GSH cells > DBA > LR > GP. Both in vivo and in vitro studies demonstrate a more intense cellular reaction to GSH tissue; this may explain the previously observed rapid cellular rejection. Also, the complete lack of response to guinea pig cells may indicate an inability of cellular recognition between these widely discordant (as measured by rejection times) species or perhaps an as-yet-unknown inhibitory mechanism.