The use of HLA transgenic mice in models of immunity and disease assumes that human MHC molecules are able to contribute toward the positive selection of the mouse TCR repertoire. As an initial step towards analysis of this we have compared the relative ability of DR alpha/E beta or E alpha/E beta complexes to induce T cell receptor (TCR) positive selection in H-2Ea and HLA-DRA transgenic mice lacking endogenous E alpha. The results show that, like E alpha/E beta, the hybrid DR alpha/E beta complexes are capable of mediating positive selection of V beta 2+, V beta 6+, and V beta 10+ cells. However, differences were found between the effects of the two transgenes. Thus, while V beta 6+ cells were efficiently selected in both H-2Ea and DRA transgenic mice, positive selection of V beta 10+ cells was less apparent in the DRA transgenic mice. Variation between Ea and DRA transgenic mice is consistent with the notion that this process is dependent on differential binding of endogenous peptides to the E alpha/E beta and DR alpha/E beta complexes. Furthermore, contrary to expectations, in neither set of mice was positive selection limited solely to the CD4+ subset. Thus, examples were found in which V beta-specific positive selection was confined to either the CD4+ or CD8+ subsets, and others in which both subpopulations were concomitantly increased. In the case of V beta 2 positive selection, H-2Ea transgenic mice showed expansion of these cells in both the CD4+ and CD8+ subpopulations while in DRA transgenic mice this occurred predominantly in the CD8+ subpopulation.