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PURPOSE To evaluate which parameters may affect endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK) by comparing eyes in the low versus high quartile of endothelial cell loss over a follow-up period of four years. DESIGN Retrospective cohort study. METHODS Donor endothelial cell density (ECD) decline was evaluated for 351 eyes of 275 patients up to four years after DMEK for Fuchs endothelial corneal dystrophy (FECD). Eyes with a postoperative endothelial cell loss in the lower quartile at all available follow-up moments were assigned to Group 1 (n=51), and those in the upper quartile to Group 2 (n=42). Multinominal regression was used to assess which covariates were related to greater ECD decline. RESULTS Mean endothelial cell loss as compared to preoperative donor ECD for the entire study group was 33 (±16)%, 36 (±17)%, and 52 (±18)% at 1, 6 and 48 months postoperatively. Endothelial cell loss of Group 1 was 12 (±7)%, 13 (±6)%, and 26 (±8)% at respectively 1, 6 and 48 months postoperatively, and 59 (±10)%, 64 (±9)%, and 75 (±5)% in Group 2. Partial graft detachment, donor death cause cardiovascular/stroke (vs cancer), postoperative complications other than graft detachment and severity of preoperative FECD (all P<0.01) showed the strongest relation with greater ECD decline. CONCLUSIONS DMEK eyes with a completely attached graft and operated in an early stage of FECD may show the lowest endothelial cell loss postoperatively.