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Penetrating keratoplasty (PK) ranks among the oldest and most common kinds of human tissue transplantation. Based on the hypothesis that reported indications for PK significantly vary between global regions and over time, the present systematic review aimed to provide a thorough overview of global PK indications as reported in peer-reviewed manuscripts.A literature search of PubMed and MEDLINE was conducted to retrieve articles published from January 1980 to May 2014. Indications for PK within 7 global regions were compared using a modified classification system for PK indications and analyzed via multivariate regression.A total of 141 publications from 37 countries were included, recording 180 865 PK cases. Postcataract surgery edema was the predominant indication in North America (28.0%) and ranked second in Europe (20.6%), Australia (21.1%), the Middle East (13.6%), Asia (15.5%), and South America (18.6%). Keratoconus was the leading indication in Europe (24.2%), Australia (33.2%), the Middle East (32.8%), Africa (32.4%), and South America (22.8%). It ranked third in North America (14.2%). Keratitis was the primary indication in Asia (32.3%). Fuchs endothelial corneal dystrophy was the fourth most common indication in North America (12.9%) and Europe (10.2%) and fifth in South America (3.8%). Multivariate analysis supported these results and revealed individual regional changes over time.Systematic analysis reveals characteristic chronological and regional differences in reported global PK indications. Leading reported indications for PK between 1980 and 2014 were keratoconus (Europe, Australia, the Middle East, Africa, and South America), pseudophakic bullous keratopathy/aphakic bullous keratopathy (North America), and keratitis (Asia).