We reexamined expression patterns of one of the best characterized mouse class Ib MHC molecules, Qa-2. Transcripts encoding glycosylphosphatidylinositol-linked and soluble forms of Qa-2 are expressed in all organs except brain. The membrane-bound Qa-2 proteins are detectable, to varying degrees, in many cell types of immunological interest: on professional antigen-presenting cells capable of inducing anti-Qa-2 allogeneic responses, on thymic epithelial cells essential for T-cell positive selection, on mature as well as immature thymocytes, in immunologically privileged sites (testis/spermatazoa), and on cells implicated in mucosal immunity (lymphoid-derived and epithelial gut cells and hepatocytes). Although Qa-2 has a nearly ubiquitous tissue distribution similar to H2-Kb and Db molecules, the relative levels of Qa-2 and class Ia displayed on cell surfaces vary in a cell-specific fashion. Analyses of primary cell lines derived from normal mouse tissues also support the conclusion that Qa-2 is present in all cells that can express class Ia antigens. In contrast, tumor lines from Qa-2-positive mice are frequently Qa-2 deficient, suggesting that the Qa-2-negative phenotype of malignant cells is selected in vivo.