PURPOSE. To determine the relationship between peripapillary scleral strain change and cumulative differential IOP exposure in nonhuman primates (NHPs) with unilateral chronic ocular hypertension. METHODS. Posterior scleral shells from 6 bilaterally normal and 10 unilateral chronic ocular hypertension NHPs were pressurized from 5 to 45 mm Hg, and the resulting full-field, three-dimensional, scleral surface deformations were acquired using laser speckle interferometry. Scleral tensile strain (local tissue deformation) was calculated by analytical differentiation of the displacement field; zero strain was assumed at 5 mm Hg. Maximum principal strain was used to represent the scleral strain, and strains were averaged over a 158-wide (~3.6-mm) circumpapillary region adjacent to the ONH. The relative difference in mean strain was calculated between fellow eyes and compared with the differential cumulative IOP exposure within NHPs during the study period. The relationship between the relative difference in scleral strain and the differential cumulative IOP exposure in fellow eyes was assessed using an F test and quadratic regression model. RESULTS. Relative differential scleral tensile strain was significantly associated with differential cumulative IOP exposure in contralateral eyes in the chronic ocular hypertension NHPs, with the bilaterally normal NHPs showing no significant strain difference between fellow eyes. The sclera in the chronic ocular hypertension eyes was more compliant than in their fellow eyes at low levels of differential cumulative IOP exposure, but stiffer at larger differential IOPs (P < 0.0001). CONCLUSIONS. These cross-sectional findings suggest that longitudinal IOP-induced changes in scleral mechanical behavior are dependent on the magnitude of differential cumulative IOP exposure.