BACKGROUND: Epithelial downgrowth is a rare complication of ocular surgery. While the features of epithelial downgrowth following corneal transplantation are well described, its association with primary graft failure has only been reported once previously. We report a case of primary corneal graft failure (PGF) associated with retrocorneal epithelial cell ingrowth. CASE PRESENTATION: A 59 year-old male underwent an uncomplicated penetrating keratoplasty for Fuchs' corneal dystrophy. The patient developed PGF, and a second transplant was performed 5 weeks after the initial surgery. The initial host corneal button and the failed corneal graft were examined with light microscopy. Histopathologic examination of the excised corneal button demonstrated multilaminar epithelial cells on the posterior corneal surface and absence of endothelial cells. DNA extraction and polymerase chain reaction (PCR) for herpes simplex virus (HSV) DNA was performed on the failed corneal graft. Polymerase chain reaction performed on the failed corneal graft was negative for HSV DNA, which has been implicated in selected cases of PGF. Three years following repeat penetrating keratoplasty, there was no evidence of recurrent epithelial ingrowth. CONCLUSION: This is only the second report of PGF associated with epithelialization of the posterior corneal button, which most likely developed subsequent to, instead of causing, the diffuse endothelial cell loss and primary graft failure