To evaluate graft detachment after Descemet membrane endothelial keratoplasty (DMEK) in pseudophakic eyes and DMEK combined with cataract surgery (triple DMEK). Analysis of 3 single-center prospective cohort studies and 1 randomized controlled trial. Participants with Fuchs' endothelial corneal dystrophy. A validated neural network for image segmentation quantified graft detachment on anterior segment OCT (AS-OCT) images 3 days after DMEK and at the 2-week postoperative visit. Area and volume of graft detachment were compared between DMEK only and triple DMEK using generalized estimating equation models and adjusting for participant age and the size of the air bubble. Area and volume of DMEK graft detachment. Among 207 participants with 270 eyes included, 75 pseudophakic eyes had DMEK only and 195 eyes had triple DMEK. A total of 147 eyes had less than one third of detachment at day 3. In 139 of these eyes (95%), detachment was still less than one third at the 2-week scan, indicating that postoperative graft detachment at 2 weeks occurred mainly in eyes with early detachment. When superimposing all 3-dimensional maps from 2 weeks after surgery, the central graft was mainly attached and detachment was located at the graft margin. The mean area of graft detachment decreased from 28% in DMEK only and 38% in triple DMEK to 16% in DMEK only and 25% in triple DMEK at the 2-week postoperative visit. At 2 weeks, the mean area of detachment was 1.85-fold higher (95% confidence interval [CI], 1.34-2.56) and the mean volume was 2.41-fold higher (95% CI, 1.51-3.86) in triple DMEK compared with DMEK. A total of 46 eyes received rebubbling procedures, with 7 eyes (9%) in the DMEK group and 39 eyes (20%) in the triple DMEK group (adjusted risk ratio, 3.1; 95% CI, 1.3-7.1), indicating that rebubbling was more common in eyes undergoing triple DMEK. Automated segmentation of AS-OCT images allowed precise quantification of graft detachment over time and identified DMEK combined with cataract surgery as a risk factor. Frequency of operative follow-up might be guided by extent of detachment in the first postoperative days after DMEK.