Purpose: The purpose of this study was to present a case series of patients with extreme corneal flattening after uneventful endothelial keratoplasty (EK): collagen compaction syndrome. Methods: Four patients (2 men, 2 women, mean age 64.8 ± 11.8 years) underwent successful EK after a period of chronic corneal edema (4–7.5 months): 3 received Descemet membrane endothelial keratoplasty after unsuccessful Descemet stripping only for Fuchs dystrophy and 1 received Descemet automated endothelial keratoplasty after prolonged pseudophakic bullous keratopathy. Results: All patients developed significant corneal flattening, affecting their vision and inducing a large hyperopic refractive outcome, best-corrected visual acuities ranging from 20/40 to 20/200. Conclusions: Chronic corneal edema may result in severe corneal flattening after EK. Preoperative duration of stromal edema might affect the outcome of EK and should, therefore, be considered in the timing of surgery. In cases of dense focal edema, including post-Descemet stripping only surgery, rescue treatment at week 8 should be considered.