To assess whether cross-linking the carrier donor cornea of the Boston Keratoprosthesis (BKPro) improves retention of the device in participants at high risk for keratolysis. Prospective, double-masked, randomized clinical trial. In this multicenter study, 68 adult participants who were scheduled for BKPro implantation were enrolled. Masked participants were randomized to receive either a cross-linked (CXL) or non-cross-linked (non-CXL) donor corneal carrier. The Kaplan-Meier event-free survival was determined by the product-limit method and compared by the log-rank test to examine whether survival curves were different between the CXL and non-CXL groups. The primary outcome of the study was time from surgery to BKPro removal. The secondary endpoint was 12-month retention rate. A total of 68 participants were enrolled and randomized 1:1 to each group. The average age at the time of surgery was 62 (range=24-89) years, and 42 participants (62%) were male. The overall BKPro retention rate was 70% during a mean follow-up time of 93 (range=6-201) weeks. Twenty BKPros were removed, 10 in the CXL group and 10 in the non-CXL group, with 18 requiring removal because of sterile keratolysis. There was no difference in the time to removal between the groups during the study (P=.910). At 12 months, there was no significant difference in the retention rate in the CXL group (94%) vs the non-CXL group (82%, P=.150). In this prospective study, cross-linking of the carrier cornea prior to BKPro implantation did not reduce the incidence of sterile keratolysis or increase device retention among participants at high risk for retention failure.