AIM: To evaluate the effects of genipin cross-linking on bullous keratopathy in rabbits. METHODS: Nine female New Zealand white rabbits with bullous keratopathy were used as an experimental model. They were randomized into three groups. Corneas in Group A (treatment group, n=3) were immersed in 0.25% genipin at 24℃ for 40min; those in Group B (control group, n=3) were immersed in 0.9% sodium chloride solution at 24℃ for 40min; and those in Group C (blank control group, n=3) received no treatment. Follow-up examinations were performed within 2wk after treatment, including slit-lamp microscopy, central corneal thickness (CCT), evaluations of body weight and stress responses, histopathological analyses, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) for detecting stromal cell apoptosis. RESULTS: Compared to Groups B and C, remission of corneal edema, corneal healing, disappearance of epithelial bullae, a significant decrease in CCT (P<0.05), and a significant increase in body weight (P<0.05) were found in Group A. Animals in Group A became more active and showed less aggression and violent resistance behavior. More regular and dense arrangement of collagen fibers in the corneal stroma and formation of blue strips of cross-linking products were observed in Group A. Cell apoptosis occasionally occurred in the corneal stroma of Group A, while no cell apoptosis was observed in Groups B and C. CONCLUSION: Genipin cross-linking treatment for bullous keratopathy in rabbits results in remission of corneal edema and relief of pain. We hypothesize that genipin cross-linking strengthens collagen fibers in corneal stroma to avoid the formation of corneal edema and bullae.