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PURPOSE To identify whether intraoperative hyphema from the peripheral iridotomy during Descemet membrane endothelial keratoplasty (DMEK) is associated with anticoagulant or antiplatelet use, age, combined phacoemulsification, or adverse outcomes. SETTING Price Vision Group, Indianapolis, Indiana, USA. DESIGN Retrospective case series. METHODS Data were obtained from consecutive DMEK cases with an intraoperative iridotomy from July 2015 through July 2016. Hyphema was classified as negative or positive (small or large). Associations with possible risk factors and with transplant outcomes were assessed. RESULTS Of 445 cases, 262 (59%) were negative for hyphema and 183 (41%) were positive. The proportion of patients who used preoperative anticoagulant or antiplatelet medication did not differ significantly with the hyphema classification (negative hyphema 42%, small hyphema 34%, large hyphema 46%) (P = .31). Likewise, recipient age was not a risk factor for hyphema (P = .085). Hyphema was more likely in cases combined with phacoemulsification than in single DMEK procedures (relative risk, 1.5 [95% confidence interval, 1.2-1.9]). Hyphema was not associated with postoperative rebubbling rates (negative hyphema 10.5%, small hyphema 10.3%, large hyphema 8.0%) (P = .33), 6-month endothelial cell loss (mean = 29%, P = .19), or 6-month visual acuity (mean = 20/25 Snellen in all hyphema groups, P = .98). CONCLUSIONS Preoperative anticoagulant or antiplatelet use was not a significant risk factor for hyphema. The risk for hyphema was increased somewhat when DMEK was combined with cataract surgery. Intraoperative hyphema did not significantly affect the rebubbling rate, endothelial cell loss, or visual acuity outcomes.