Previously it was shown that including smaller inset regions of less stiff material in the larger O-ring section at locations of high stress results in lower strain energy density in the section. This lower energy content is expected to lead to improved long-term seal performance due to less permanent material deformation and so less loss of seal-housing contact pressure. The shape of the inset region, the time-dependent change in material properties, and hence change in seal behavior over time in use were not considered. In this research experimental and numerical simulation studies were conducted to characterize the time-dependent performance of O-ring section designs with small inset regions of different mechanical behaviors than the larger surrounding section. Seal performance in terms of the rate of loss of contact pressure of modified designs and a baseline elastic, one-material design was calculated in finite element models using experimentally measured time-dependent material behavior. The elastic strain energy fields in O-ring sections were calculated under applied pressure and applied displacement loadings. The highest stress, strain, and strain energy regions in O-rings are near seal-gland surface contacts with significantly lower stress in regions of applied pressure. If the size of the modified region of the seal is comparable to the size of the highest energy density region, the shape of the inset is not a major factor in determining overall seal section behavior. The rate of loss of seal-housing contact pressure over time was less for the modified design O-ring sections compared with the baseline seal design. The time-dependent performance of elastomeric seals can be improved by designing seals based on variation of mechanical behavior of the seal over the seal section. Improvement in retention of sealing contact pressure is expected for seal designs with less stiff material in regions of high strain energy density.