PURPOSE: To evaluate the current indications and clinical outcomes for penetrating keratoplasty (PK) in the United States. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients from the IRIS® Registry (Intelligent Research in Sight) without a history of prior keratoplasty who underwent PK from October 2015 through December 2017. METHODS: Corneal graft survival, transplant-specific outcomes, and postoperative complications were evaluated for all patients based on International Classification of Diseases codes. Postoperative graft survival and best-corrected visual acuity (BCVA) were stratified by reported presumed surgical indication. Risk factors for corneal graft failure were evaluated using multivariable analysis. MAIN OUTCOME MEASURES: Postoperative graft survival and BCVA. RESULTS: A total of 4061 patients were included (mean age at surgery, 60.2 years; 51.5% female; 60.6% White). At 5 years, the highest probability of graft failure was observed in patients with complications of ocular prosthetic device (42.9%), trauma or perforation (31.4%), and corneal edema (23.2%), whereas the lowest probability was seen in patients with corneal ectasia (8.5%). Overall graft survival probability at 5 years was 81.1%. Among surgical indications, the highest probability of visual acuity worse than 20/70 was seen in patients with corneal edema (91.3%), corneal opacities (90.9%), and trauma or perforation (87.1%), and the lowest probability was seen in patients with corneal ectasia (67.2%). Half of all patients (53.4%) showed improved BCVA of more than 2 lines after 3 years. CONCLUSIONS: Compared with previous literature, PK was less frequently performed for corneal ectasiae in this study. Although PK in patients with corneal ectasia was associated with increased graft survival and better long-term BCVA compared with other surgical indications in this study, worse outcomes including lower overall graft survival were observed compared with previous literature outcomes for corneal ectasia. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.