To examine the clinical pathology and management of Paecilomyces lilacinus keratitis.Observational case series, literature review, and laboratory study.Characteristics and outcome of 17 patients with laboratory-confirmed Paecilomyces keratitis treated at 2 referral centers were combined with 25 previously reported cases. Experimental models were developed by topically inoculating a human corneal isolate of P. lilacinus onto murine eyes and onto human donor corneas.Of 42 reported eyes with Paecilomyces keratitis, 13 (31%) were associated with chronic keratopathy or previous ocular surgery, 11 (26%) followed corneal trauma, and 10 (24%) occurred in soft contact lens wearers. Medical cure occurred in 13 (31%), including 9 of 31 eyes (29%) treated with natamycin or amphotericin B. Penetrating keratoplasty or other surgery was performed in 29 (69%). In vitro testing of P. lilacinus indicated resistance to natamycin and amphotericin B but susceptibility to ketoconazole and voriconazole. Experimental inoculation after superficial scarification established moderately severe corneal paecilomycosis by hyphae and conidia in immunosuppressed mice and in explanted donor corneas.P. lilacinus is an emerging fungal pathogen that infects corneal tissue by filamentous invasion with occasional intrastromal sporulation. P. lilacinus keratitis does not reliably respond to natamycin or amphotericin B and has often required therapeutic keratoplasty, but topical azole antifungal agents such as voriconazole appear promising.