Purpose To report two cases of polymicrobial keratitis following corneal collagen cross-linking for keratoconus and to review the literature. Methods Retrospective case note and literature review. Results The first case involved a 27-year-old male who presented with amebic corneal ulcers 3 days after the collagen cross-linking procedure. Some gram-negative (gram-ve) cocci were found upon staining, and cysts were observed by confocal microscopy at 7 days after surgery. Acanthamoeba infection mixed with gram-ve organisms was diagnosed. In the second case, a 14-year male developed Staphylococcus aureus corneal infection with anterior chamber empyema 3 days after the collagen cross-linking procedure for keratoconus. Occasional gram-positive (gram + ve) cocci and gram-ve bacilli were observed under a microscope. The mixed keratitis in the two patients resolved after systemic and topical antibiotic therapy, but the infection ultimately resulted in corneal scarring. Follow-up keratoplasty was needed to improve vision acuity in both patients. Conclusion Although ultraviolet irradiation and the reactive oxygen released by riboflavin during collagen cross-linking have bactericidal effects, a lack of a corneal epithelial barrier, bandage contact lens usage, perioperative hygiene, and an abnormal immune state are risk factors for infectious keratitis after collagen cross-linking. Perioperative management of collagen cross-linking is important to prevent infection.