Fully H-2 incompatible radiation chimeras were prepared using BALB congenic mice. Such chimeric mice were immunized in vivo against histocompatibility antigens of the C57BL/10Sn (B10) background in association with either of the parental H-2 haplotypes, and their spleen cells subsequently boosted in vitro with the same minor antigens. Strong H-2-restricted cytotoxic activity against minor antigens was detected, and the specificity of the restriction could be to the H-2 haplotype of the donor or the host depending on the cells used for priming or boosting. Cross priming could also be demonstrated in these mice. The results show that fully allogenic radiation chimeras can produce H-2-restricted T-cell responses to minor histocompatibility (H) antigens, and are discussed in relation to contrasting results recently obtained against viral antigens.