THE repertoire of mature class II-restricted T cells is generated through a complex process of selection whereby early T cells confront class II molecules in the thymus, especially on epithelial cells 1-3. Expression of class II molecules on such cells is prominent both in the cortex and in the medulla 4,5. We have identified a novel class II molecule, H-2O, which is expressed only in epithelial cells of the thymic medulla and in B cells. The unusual tissue distribution and the nonpolymorphic nature of H-2O suggest that its function is different from that of classical class II molecules.