AIM: To investigate indications, surgical challenges, and outcome of Descemet-membrane endothelial keratoplasty (DMEK) in patients with retinal comorbidities (RC). METHODS: In a prospective cohort study, 8 eyes of 8 DMEK-patients with known RC were compared to 38 eyes of 38 DMEK-patients without RC. The duration of surgery, the degree of difficulty graded by the surgeon, and the complications through DMEK-surgery were analyzed for each patient. The best-corrected visual acuity (BCVA), the endothelial cell count, the intraocular pressure, and the subjective satisfaction was evaluated after a 6-month follow-up. Data were compared applying the non-parametric Wilcoxon-, Chi-square- and Fisher´s-exact-test with P≤0. 05 as level of significance. RESULTS: RC-patients had dry age-related macular degeneration (n=4) or history of pars-plana vitrectomy (n=4). The main indication for DMEK was pain due to bullous keratopathy for the RC-patients (n=7, 88%) and visual impairment due to Fuchs endothelial keratoplasty for the non-RC-patients (n=33, 87%). The BCVA increased for both groups (P=0.01, P<0.001) and all corneas cleared. For the RC-patients, the subjective satisfaction improved significantly (P=0.02). Oil-filling and missing support of the vitreous body complicated surgery in vitrectomized eyes. CONCLUSION: DMEK is a favorable technique to treat endothelial disorders even if patients suffer from a retinal comorbidity. By enhancing the corneal clarity, it enables retinal examination or intraocular surgery and increases the patients´ satisfaction. However, in vitrectomized or silicone-oil filled eyes, the duration of surgery and degree of complexity are increased. An experienced surgeon should perform DMEK in these patients. Clinical trial registration number: DRKS00007566.