To evaluate the use of combined topical and intracameral anesthesia for Descemet's stripping automated keratoplasty (DSAEK). This was a retrospective comparative cohort analysis consisting of 10 eyes in 10 consecutive patients undergoing DSAEK surgery with combined topical and intracameral anesthesia. These cases were compared with 21 randomly selected controls during the same time period undergoing DSAEK surgery performed under retrobulbar anesthesia. Incidence of intraoperative and postoperative complications, and endothelial cell counts were compared. In all cases, DSAEK was completed without intraoperative complications. All patients tolerated the procedure well. There were 6 cases of postoperative graft dislocation requiring rebubbling, and no cases of primary failure or endophthalmitis. No significant difference in endothelial cell counts was found at final follow-up. Short-term results suggest that combined topical and intracameral anesthesia is as safe and effective for DSAEK in cooperative patients when compared to retrobulbar anesthesia. It may thereby be an alternative anesthetic modality for patients in whom retrobulbar or peribulbar anesthesia may be risky or contraindicated.