Femtosecond laser is as a novel tool for performing precise descemetorhexis in descemet membrane endothelial keratoplasty (DMEK) surgery. In DMEK surgery, the recipient’s Descemet membrane is peeled to allow adherence of the donor DMEK tissue to the recipient’s stroma. Complete removal of the recipient’s Descemet membrane at the transplant site is crucial, since remnant tags and islands of Descemet’s tissue might interfere with DMEK graft attachment. The authors did a retrospective, interventional study to compare the efficacy of femtosecond laser-assisted-Descemet membrane endothelial keratoplasty (F-DMEK) to that of manual Descemet membrane endothelial keratoplasty (M-DMEK) and three year outcome. Sixty-one eyes were included, 16 in the F-DMEK group, and 45 in the M-DMEK group. The two groups were chronologically matched to avoid chronological bias related to the surgeon’s learning curve. The data collected in this study included best spectacle-corrected visual acuity (BSCVA), intraoperative and postoperative complications, corneal donor characteristics, and endothelial cell density (ECD).The descemetorhexis diameter was of same size as graft diameter in the F-DMEK group and was 0.25mm larger than graft diameter in the M-DMEK group. Graft diameter in both groups was sized 3mm less than the corneal diameter. All patients had the same postoperative treatment and follow-up. Rebubbling was performed within 24 hours in eyes with Descemet membrane detachment spanning more than one-third of the DMEK graft area or later on if there was an unresolved Descemet membrane detachment that was causing persistent corneal oedema. All descemetorhexis cuts with femtosecond laser were complete. BSCVA improvement did not differ significantly between the groups at one, two, and three years (P=0.849, P=0.465 and P=0.936, respectively). Rates of significant detachment in F-DMEK and M-DMEK were one of 16 eyes (6.25%) and 16 of 45 eyes (35.6%) (P=0.027). Rebubbling rates were one of 16 eyes (6.25%) and 15 of 45 eyes (33.3%) (P=0.047). Cell-loss rates following F-DMEK and M-DMEK were 26.8% and 36.5% at one year (P=0.042), 30.5% and 42.3% at two years (P=0.008), 37% and 47.5% at three years (P=0.057), respectively. Graft failure rate was 0% in F-DMEK and 8.9% in M-DMEK (all were primary failures; P=0.565). The authors conclude that F-DMEK showed good efficacy and fewer complications like detachment, rebubbling and cell loss compared to M-DMEK.