PROJECT SUMMARY/ABSTRACT Although endothelial keratoplasty is one of the most commonly performed transplant surgeries, it is unknown which technique provides optimal visual acuity outcomes while minimizing endothelial cell loss and complications. Post-operative endothelial cell counts have been shown to correlate with risk of subsequent graft failure, with significant cost to individual patients and society. Topical rho-kinase inhibitors such as ripasudil 0.4% may play an important role in maintaining endothelial health after keratoplasty. Here we propose the Descemet Endothelial Thickness Comparison Trial (DETECT), a randomized, outcome- masked, multi-center, four-arm clinical trial with a 2x2 factorial design. The purpose of this study is to determine differences in visual outcomes between two types of corneal transplant surgeries, ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), and to determine the effect of rho-kinase inhibitors on endothelial cell counts after keratoplasty. Patients presenting to Oregon Health & Science University, Stanford University, NorthShore University HealthSystem, University of Maryland, and to Kaiser Permanente Northern California with endothelial dysfunction who are good candidates for either UT-DSAEK or DMEK will be eligible for inclusion. Participants will be randomized to one of four treatment groups in this 2x2 factorial design study: Endothelial Keratoplasty UT-DSAEK DMEK Adjuvant Topical Medication Ripasudil 0.4% UT-DSAEK + 0.4% ripasudil DMEK + 0.4% ripasudil Placebo UT-DSAEK + placebo DMEK + placebo This approach is innovative for a number of reasons including its testing of a novel treatment, ripasudil 0.4%, and the randomization of surgery, which is relatively rare. It is aligned with the priorities of the NEI, studying new high-resolution imaging techniques such as endothelial cell imaging, anterior-segment optical coherence and Pentacam Scheimflug imaging, to guide post-operative treatment and as potential surrogate trial endpoints in future trials. This world class team of collaborators have a proven track record for executing large NEI- funded trials in ophthalmology, and are well positioned to answer the two important questions presented in this proposal.