PURPOSE: The aim of this study was to report a case series of epithelial downgrowth associated with Descemet stripping automated endothelial keratoplasty (DSAEK) and to explore the origin of the anterior chamber corneal epithelium. METHODS: This is a case series and literature review. RESULTS: Three histopathologically confirmed cases of epithelial downgrowth after DSAEK were identified. All cases were treated with argon laser ablation, intracameral 5-fluorouracil, and intraocular surgery. Recurrent epithelial downgrowth occurred in 2 of 3 cases. Fluorescent in situ hybridization analysis with fluorescent probes for X and Y chromosomes was used to analyze epithelial downgrowth tissues in all cases. All 3 cases were consistent with donor tissue origin of epithelial downgrowth tissue. However, this could only be confirmed in 1 case. The donor and the recipient were the same sex in 2 cases; thus, no definitive conclusion was possible in these patients. CONCLUSIONS: There have been multiple reports of epithelial downgrowth after DSAEK. We include additional evidence to support the role of donor tissue corneal cells as the source of epithelium in some of these cases. It is surprising that donor tissue would be tolerated immunologically by the patient in these cases. We propose that tolerance for donor epithelium may be mediated through anterior chamber-associated immune deviation.