A 49-year-old man, who underwent Penetrating Keratoplasty (PK) for pseudophakic bullous keratopathy 6 months previously, presented with progressive mydriasis and angle closure. A diagnosis of epithelial downgrowth into the anterior chamber was made. We decided to treat the increase in intraocular pressure (IOP) by performing the implantation of an Ahmed valve plus injection of 5-fluorouracil (5-FU) for anterior chamber toilette and a posterior capsulotomy to solve the flattened anterior chamber. Aqueous humor cytology and iris biopsy confirmed the diagnosis. The drainage device reduced IOP only temporarily . Anterior vitrectomy and posterior capsulotomy resolved the flat anterior chamber. The drug 5-FU did not completely stop cellular proliferation, although no involvement of the vitreous cavity was noticed after 5 years of follow-up. Progressive pupillary enlargement may be the first sign of epithelial downgrowth in the anterior chamber. This is a rare complication of PK and one that is difficult to manage.