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To investigate the novel application of tissue microarray (TMA) technology to corneal disease and to report altered protein expression of senescence-associated cyclin-dependent kinase inhibitors p21 and p16 in Fuchs endothelial corneal dystrophy (FECD).A TMA including 208 cores was generated from paraffin-embedded tissues, including corneal buttons of 50 FECD and 5 keratoconus patients retrieved after penetrating keratoplasty, 10 autopsy globes with nonpathologic corneas, and nonocular control specimens. TMA sections were immunolabeled for p21 and p16 and analyzed using a 9-grade scoring system (0–8). Result validation was performed by immunolabeling of individual whole tissue sections. Corneal endothelial p21 and p16 expression levels in FECD specimens compared with controls served as main outcome measures.TMA immunohistochemical analysis disclosed increased endothelial expression levels of nuclear p21 in FECD specimens (P < 0.05) and an altered endothelial p16 expression pattern. Immunolabeling of whole tissue sections showed statistically significant endothelial overexpression of both proteins (p21 and p16, P < 0.05).The present study introduces TMA technology as a valuable tool for molecular high-throughput profiling of corneal tissues. It demonstrates p21 and p16 overexpression in the corneal endothelium of genetically undifferentiated FECD patients supporting a role of cellular senescence in the pathogenesis of FECD.