PURPOSE: To evaluate 5-year endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK), compare it with reported rates for Descemet-stripping endothelial keratoplasty (DSEK) and penetrating keratoplasty (PKP), and investigate potential association between cell loss and air reinjection. SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Retrospective comparative case series. METHODS: Consecutive DMEK procedures performed between March 2008 and April 2013 were reviewed. The inclusion criterion was at least 6 months of follow-up. Endothelial cell density was recorded preoperatively and 1, 3, and 6 months and annually through 5 years postoperatively. Potential association between air reinjection and endothelial cell loss was evaluated by repeated measures analysis of variance. RESULTS: Of the 926 procedures performed, 673 eyes met the inclusion criterion. Indications for DMEK included Fuchs dystrophy (n = 595), pseudophakic corneal edema (n = 30), failed endothelial keratoplasty (n = 39), and failed PKP (n = 9). The median endothelial cell loss was 26% at 1 month, increasing to 39% at 5 years in cross-sectional and longitudinal analyses. Cell loss was similar in eyes with no (n = 471) or 1 (n = 155) air reinjection and significantly higher in eyes with 2 or more air reinjections (n = 47, P=.017). CONCLUSIONS: The median 5-year cell loss of 39% with DMEK compared favorably with prior reports of DSEK (53%) and PKP (70%) performed for similar indications. Similar to DSEK, most DMEK cell loss was associated with the surgical procedure itself; subsequent cell loss occurred at a slower rate than after PKP. Cell loss was not significantly increased in eyes with a single air reinjection. (C) 2014 ASCRS and ESCRS