AIM: To evaluate the effect of posterior sclera collagen cross-linking induced by riboflavin-ultraviolet A (UVA) on form-deprived myopia in guinea pigs. RESULTS: After 4wk, the interocular difference of refractive error were -0.11±0.67, -2.93±0.56, 1.10±0.58, and -1.63±0.41 D in the NOR, FDM, NOR+CL, and FDM+CL groups respectively. Mixed-effect linear model revealed significant effect of FDM (P<0.01) and CL (P<0.001). Also, after 4wk, the interocular difference of axial length were 0.01±0.04, 0.29±0.07, -0.13±0.06, and 0.11±0.05 mm in the NOR, FDM, NOR+CL, and FDM+CL group. Mixed-effect linear model revealed significant effect of FDM (P<0.001) and CL (P<0.01). As for corneal curvature, significant interocular difference have not found between any of the two groups. At the end of this experiment, the ultimate stress and elastic modulus were found significantly increased in both CL groups. But no difference was found in the groups without cross-linked. There was no abnormality observed in the retina and RPE cells of the treated eyes. CONCLUSION: The posterior sclera collagen cross-linking induced by riboflavin-UVA can slow down the progress of myopia and increase the sclera biomechanical strength in the guinea pig model of form-deprived myopia.