Purpose To determine if central donor lenticle thickness as measured by slit-lamp optical coherence tomography (SL OCT; Heidelberg Engineering, Heidelberg, Germany) is predictive of primary donor failure in patients undergoing Descemet stripping automated endothelial keratoplasty (DSAEK). Design Retrospective cross-sectional study. Methods Eighty-four patients who underwent DSAEK surgery by 2 surgeons (D.C.R. and J.A.S.) were enrolled. At each postoperative visit (postoperative day 1, week 1, month 1, and month 2), an SL OCT scan was obtained. Statistical differences in SL OCT measurements of successful and failed DSAEK procedures were measured using the Student t test. A successful DSAEK surgery was defined as having an anatomically attached, clear recipient corneal stroma and donor lenticle compatible with good vision 2 months after surgery. A failed DSAEK surgery was defined as an attached donor lenticle with SL evidence of corneal edema and thickening visible at 2 months or more. Results Ninety-three eyes of 84 consecutive patients who underwent DSAEK surgery also underwent postoperative SL OCT. After 2 months of follow-up, 82 (88%) procedures were successful and 11 (12%) procedures were failures. The average donor lenticle thickness in successful DSAEK eyes was 314 ± 128 μm on postoperative day 1 as compared with failed DSAEK eyes, which averaged 532 ± 259 μm (P = .0013). This was independent regardless of whether the lenticle was attached on the first postoperative visit. Seventy-nine (98%) successful DSAEK eyes had a lenticle thickness of ≤ 350 μm at the 1-week visit. All of the failed DSAEK eyes (11 eyes) had a lenticle thickness ≥ 350 μm at the 1-week postoperative visit. Statistically significant differences in SL OCT thickness measurements were seen between successful and failed DSAEK cases at all examinations after postoperative week 1. Conclusions Corneal thickness measurements made with SL OCT are an important predictor of DSAEK failure in both attached and detached lenticles within the first week of surgery. DSAEK lenticle thickness of 350 μm or less at 1 week had a predictability of success of more than 98%.