PURPOSE: To describe the safety and effectiveness of using autologous serum-based eye drops for the treatment of severe dry eye and persistent corneal epithelial defect. METHODS: Literature searches of the PubMed and Cochrane Library databases were conducted most recently in March 2019. The searches identified 281 citations, which were reviewed in abstract form. Of these, 48 were selected for a full-text review, and 13 met the inclusion criteria and were assigned a quality-of-evidence rating by the panel methodologist. Eight of these studies were rated level II and 5 were rated level III; there were no level I studies. RESULTS: This analysis included 10 studies of the use of autologous serum-based eye drops for severe dry eye disease and 4 studies of persistent epithelial defect. Several studies showed good effectiveness, with some improvement in symptoms, signs, or both. Eight of the studies reported improved symptoms for severe dry eye disease, and all noted improvement in at least 1 clinical sign. For persistent epithelial defects, all of the studies showed improvement, with 3 of the 4 demonstrating an improvement rate of more than 90%. Adverse events were rare. CONCLUSIONS: Although autologous serum-based tears may be effective in the treatment of severe dry eye and persistent epithelial defect, conclusions are limited owing to the absence of controlled trials.