We have used C.B-17 severe combined immune deficiency (SCID) mice to study the repopulation of intestinal intraepithelial cells in these mice. We have found that intestinal intraepithelial lymphocytes (IELs) injected into SCID mice preferentially repopulate the intestinal epithelium. About 5 weeks after injection we can detect significant numbers of IEL in repopulated SCID mice. Repopulation occurs in approximately 70% of the injected mice and the amount of recovered cells per mouse is variable. The recovered cells are of donor-type origin and exhibit a typical IEL phenotype. The donor-type T lymphocytes that can sometimes be found in other organs of IEL-repopulated SCID mice are generally of low number. They are not stained with antibodies against IEL-specific markers and their phenotypes appear to be more typical for T cells normally found in these sites. In contrast, the intestinal epithelium of SCID mice cannot be efficiently repopulated with lymphocytes using cells of other organs including thymocytes, Peyer's patch lymphocytes, and bone marrow cells. From our data we conclude that intestinal IELs are confined to the intestinal epithelium and possibly contain a precursor-type cell that preferentially regenerates cells of its own population.