Descemet stripping automated endothelial keratoplasty (DSAEK) in eyes with complex anterior segment pathology or previous intraocular surgery is at risk of surgical complications and graft failure. We evaluated the use of the EndoGlide donor insertion device for DSAEK in these complex cases. This was a retrospective interventional series of 45 consecutive eyes with endothelial dysfunction and higher risk ocular comorbidities that underwent DSAEK with the EndoGlide. We included eyes with aphakia, glaucoma surgery, prior vitrectomy, anterior chamber intraocular lenses, failed cornea grafts, and primary angle closure glaucoma. Demographic and clinical details, intraoperative and postoperative complications, and postoperative graft clarity, and endothelial cell density (ECD) loss were documented. The average age was 62 years (range, 16-88 years), and the majority were Chinese (n = 28). The commonest risk factors identified were previous trabeculectomy (n = 13) and failed penetrating keratoplasty (n = 12). Preoperative donor ECD averaged 2790 ± 230 cells per square millimeter and modal graft diameter was 9.0 mm (range, 7.75-9.75 mm). One eye (2.2%) had primary graft failure, and 3 eyes (6.7%) had graft dislocation. Another 3 eyes suffered late graft failure within the first year and 2 were in eyes with an anterior chamber intraocular lenses. At 6 months, the mean ECD was 2363 + 242 cells/mm2 and the mean ECD loss was 17.9% (n = 16). By 12 months, the mean ECD was 2098 + 462 cells/mm2 and the mean ECD loss was 27.0% (n = 20). Donor insertion with this device can help address inherent intraoperative challenges and minimize endothelial cell damage during DSAEK in complex cases.