Purpose: The purpose of this study was to evaluate 5-year safety and efficacy outcomes of femtosecond-enabled Descemet membrane endothelial keratoplasty (F-DMEK) in patients with Fuchs’ endothelial dystrophy (FED). Methods: This was a retrospective study, including patients with FED and cataract who underwent either F-DMEK (16 eyes of 15 patients) or manual DMEK (M-DMEK) (42 eyes of 37 patients) combined with cataract extraction. Outcome measures included visual acuity, graft detachment, graft survival, and endothelial cell loss. Results: The average follow-up in F-DMEK and M-DMEK was 57.1 6 12.4 months and 58.5 6 17.3 months, respectively (P = 0.757). The rates of primary failure (0% vs. 9.5%, P = 0.567), secondary failure (0% for both), and graft rejection (0% vs. 7.1%, P = 0.533) did not differ significantly between the groups. Improvement in best spectacle-corrected visual acuity was similar in F-DMEK and M-DMEK (0.32 6 0.27 logarithm of the minimum angle of resolution and 0.35 6 0.44 logarithm of the minimum angle of resolution, respectively, P = 0.165) and persisted at 2, 3, 4, and 5 years and at the last follow-up. The rates of graft detachment and rebubbling were significantly lower with 6.25% in F-DMEK and 33.3% in M-DMEK (P = 0.035). Cell-loss rates were lower in F-DMEK compared with M-DMEK throughout the follow-up, significantly so up to 2 years with a difference of 8.6% at 1 year (P = 0.023), 11.8% at 2 years (P = 0.021), 7.6% at 3 years (P = 0.088), 5.8% at 4 years (P = 0.256), 13.6% at 5 years (P = 0.169), and 7.1% at the final follow-up (P = 0.341). Conclusions: F-DMEK had an excellent safety and efficacy profile which was maintained over 5 years of follow-up. Lower endothelial cell-loss rates in F-DMEK compared with M-DMEK may help extend the duration of graft survival.