In this report the authors present evidence for the generation of H-2-nonrestricted cytotoxic T lymphocytes (CTL) specific for determinants encoded in the Qa-1 region of the 17th chromosome. B10.BR (Qa-1a) CTL primed in vivo and restimulated in vitro with H-2-identical AKR, C3H, or CBA (Qa-1b) splenocytes lysed Qa-1b targets, irrespective of their H-2 haplotypes. Immunizations in the reverse direction produced H-2-nonrestricted CTL that lysed Qa-1a but not Qa-1b targets. Mapping experiments with target cells from B6 congenic mice confirmed that the locus controlling these reactions lies in the Qa-1 region. Although it has been difficult to raise antisera against Qa-1b gene products, these cytotoxic data argue that the recognition of the products of the Qa-1 region is bidirectional. Determinants encoded in the Qa-1 region, detected serologically or by CTL, were found on both T and B cell blasts. The authors also found that an antiserum against Qa-1a gene products specifically blocked the cell-mediated killing of Qa-1a targets, thus suggesting that CTL and antibodies bind products of the same genetic locus. Whether Qa-1 is a single locus or a complex of serologically and CTL-defined genes, the nonrestricted nature of anti-Qa-1 CTL suggests important functional and structural similarities between Qa-1 and the murine major histocompatibility complex.