Adjustment of histocompatibility-based allocation criteria in kidney transplantation from HLA matching to matching on the basis of cross-reactive groups (CREG), was recently suggested to be a good alternative to transplant with more "well-matched" kidneys, without negatively influencing graft survival. Because graft rejection is often mediated by cytotoxic T cells (CTLs), we investigated whether a beneficial effect of CREG matching is reflected in vitro by lower CTL precursor frequencies (CTLpf). Therefore, CTLpf were determined in a group of healthy individuals and analyzed with respect to the number of HLA and CREG mismatches. A clear correlation was found between the number of HLA mismatches and the CTLpf, that is, the lowest mean frequency in case of 0 HLA-A, B mismatches (66 CTL precursors per 10(6) cells) and the highest in combinations with 4 HLA mismatches (mean = 303 CTLp/10(6) cells). The situation was different in the case of CREG mismatches. Although the highest frequency was found in the group of 4 CREG mismatches, no significant differences were observed between 0, 1, and 2 CREG mismatches. High CTLpf, up to 430/10(6), were even seen in the case of 0 CREG mismatches. Also within a well-defined group of single HLA-A or HLA-B mismatches no difference in CTLpf were observed between the subgroups with 0 vs. 1 CREG mismatches. The present study showed that in vitro the CTLpf correlates better with HLA than with CREG matching. These data are consistent with findings reported by several groups that matching for the CREG does not benefit transplant outcome.