Our laboratories have focused on the role of the tetraspanin CD81 in the regulation of mitotic activity. Previously we have shown that antibodies directed against CD81 can block the proliferation of cultured retinal pigment epithelial (RPE) cells. The present study investigates the role of this protein by analyzing the structure of the adult retina in mice with a null mutation of cd81. Adult cd81^−/− mice were produced by crossing two inbred strains, NIHS‐BC/Tac and 129X1/SvJ, carrying the cd81 mutation as heterozygotes (+/−). Seven cd81^−/− mice and 11 wildtype (cd81^+/+) littermates were anesthetized and perfused with paraformaldehyde. The eyes were removed and processed for examination by light and electron microscopy. In general, the retinas of the cd81^−/− mice appeared normal. However, upon close examination, there was an 18% increase in the number of RPE nuclei in the cd81^−/− mice. The photoreceptor layer of the cd81^−/− mice was significantly thinner than that of the wild‐type mice, even though there was no difference in the total thickness of the retinas in the two groups of mice. At the electron microscopic level we did not observe any differences in cell–cell junctions in the retinas of the cd81^−/− mice as compared to their wild‐type littermates. These data support a role for CD81 controlling cell‐cycle and the number of RPE nuclei in the mouse retina. © 2004 Wiley‐Liss, Inc.