Poly(etherurethane urea) (PEUU) elastomers, with their broad range of mechanical properties and high biocompatibility, are used clinically for medical applications. However, the possibility exists for the ether soft segment of PEUU to degrade in long-term uses. To retard degradation, antioxidants that scavenge reactive oxygen intermediates are added. In this study, we incorporated dehydroepiandrosterone (DHEA), which functions by the alternate mechanism of modulating or down-regulating adherent macrophage activity, to retard the biodegradation of PEUUs. Biocompatibility of PEUU samples containing 1% DHEA, 5% DHEA, and 5% vitamin E (alpha-tocopherol) by weight were studied in vivo and in vitro. The biocompatibility was initially evaluated by examination of the inflammatory cellular exudate. Compared to PEUU without additives and PEUU with 5% vitamin E, the addition of 5% DHEA to PEUU caused a decrease in the total leukocyte exudate concentration at 4 days. The addition of 5% DHEA also caused lower macrophage adhesion and FBGC formation compared to the other materials at 7 days. Despite these short-term effects, the biocompatibility at later time points (14, 21, and 70 days) was similar for all materials. Transmission infrared analysis of the materials revealed that more than 70% of the DHEA had leached out of the samples by 3 days implantation. Furthermore, through attenuated total reflectance Fourier transform analysis and scanning electron microscopy, it was determined that unlike vitamin E, DHEA did not enhance long-term PEUU biostability. The effect of DHEA on inflammatory cell activity appeared to be dose dependent, with improved biocompatibility in vivo for higher loading levels of DHEA, but the overall effect was limited owing to the rapid diffusion of the water-soluble DHEA from the PEUU.