The purpose of this study was to describe the incidence of graft detachment after Descemet membrane endothelial keratoplasty (DMEK) without postoperative supine posturing. A total of 106 eyes of 84 patients with Fuchs endothelial corneal dystrophy or bullous keratopathy (BK) were operated by a single experienced surgeon with DMEK with a 99% anterior chamber air bubble fill, recovered in an upright (seated) position, and then discharged without instructions to remain supine. Postoperatively, all eyes were evaluated for graft detachment through anterior segment optical coherence tomography at predetermined intervals (1 d, 1 wk, and 1 mo). Detachments were regarded as clinically significant if they subtended 30% of the total graft surface area or involved the visual axis. Clinically significant graft detachments were observed in 23 of 106 eyes (22%) in the no-supine posturing cohort, including 22 of 85 eyes (26%) operated for Fuchs endothelial corneal dystrophy and 1 of 21 eyes (5%) operated for BK. Compared with a historical comparison group of eyes undergoing DMEK with 48 hours of postoperative supine posturing, the risk of graft detachment was not increased. In both cohorts, 6% of operated eyes required regrafting for either persistent detachment or primary graft failure. No additional intraoperative or postoperative complications were experienced. Particularly in eyes operated for BK, the supine posturing requirement after DMEK may be eliminated without increasing the absolute risk for clinically significant graft detachment.