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To evaluate the clinical outcome of 500 consecutive cases up to 2 years after Descemet membrane endothelial keratoplasty (DMEK) and to assess which parameters may have influenced the clinical outcome.From a group of 500 eyes (393 patients), which underwent DMEK for Fuchs endothelial corneal dystrophy (FECD), bullous keratopathy, failed corneal transplants and other indications, clinical outcomes [best-corrected visual acuity (BCVA), central endothelial cell density (ECD), and central corneal thickness] were evaluated before, and at 6, 12, and 24 months after DMEK and postoperative complications were documented.At 12 months postoperatively, 81% of eyes reached a BCVA of ≥20/25 (≥0.8), 49% ≥20/20 (≥1.0), and 15% ≥20/18 (≥1.2) (n = 396) and remained stable up to 24 months (P = 0.828). Compared with preoperative ECD, mean postoperative ECD decreased by 37 (±18)%, 40 (±18)%, and 45 (±18)% at 6, 12, and 24 months, respectively (P < 0.05 for all time points). Surgery indication and graft attachment status were related to postoperative BCVA and ECD results. Eyes with FECD and attached grafts showed better BCVA outcomes and higher ECD (P < 0.05). Central corneal thickness decreased by 20 (±11)% to 525 (±46) μm from preoperative to 6 months postoperatively and remained stable thereafter (P > 0.05). Within the study period, retransplantation was required in 32 eyes (6.4%). Principal longer-term complications were secondary graft failure (1.4%) and allograft rejection (1.4%).Clinical outcomes remain excellent up to 2 years after DMEK, in particular for eyes operated on for FECD and with completely attached grafts.