Purpose: To report the endothelial survival over a 2-year period after 2 techniques of deep lamellar enclothelial keratoplasty (DLEK) in the treatment of enclothelial dysfunction. Design: Prospective, noncomparative, interventional case series. Participants: One hundred eyes of 88 patients with corneal edema. Methods: One hundred consecutive eyes with enclothelial failure were entered into a prospective study of enclothelial keratoplasty, and the donor central enclothelial cell density (ECD) was recorded postoperatively at 6 months (n = 98), 12 months (n = 96), and 24 months (n = 85) and then compared with the preoperative eye bank measurements. The subsets of eyes with large-incision DLEK (n = 36) and small-incision DLEK (n = 62) were also evaluated and compared. Main Outcome Measures: Preoperative and postoperative central ECDs were prospectively evaluated and the cell loss calculated for each postoperative time point. Results: The average (and standard deviation) ECD at 6 months was 2140 +/- 426 cells/mm(2), representing a mean cell loss from preoperative donor cell measurements of 25 +/- 15%. At 12 months, ECD was 2090 +/- 448 cells/mm(2) (26 +/- 16% cell loss), and at 24 months, it was 1794 +/- 588 cells/mm(2) (37 +/- 27% cell loss). The additional cell loss from 1 to 2 years was significant (P < 0.001). In the subset of large-incision DLEK eyes (n = 36), the cell loss from preoperatively to 6 months was 23%; 12 months, 22%; and 24 months, 27%. In the subset of small-incision DLEK eyes (n = 62), the cell loss from preoperatively to 6 months was 25%; 12 months, 28%; and 24 months, 43%. The cell loss from small-incision DLEK surgery was significantly greater than that from large-incision DLEK surgery at the 12-month (P = 0.013) and 24-month (P < 0.001) postoperative measurements. Conclusions: Although the initial cell loss from DLEK surgery is minimally changed from 6 to 12 months postoperatively, there is an acceleration of cell loss from 1 year to 2 years postoperatively. The small-incision DLEK technique, which involves folding of the donor tissue, results in a significantly higher enclothelial cell loss at 1 and 2 years than that found after large-incision DLEK surgery, wherein the tissue is not folded.