The in vitro biostability and biocompatibility of ethyl vinyl acetate (EVA) nanocomposites incorporating organically modified montmorillonite (organo-MMT) were investigated as new candidate material for biomedical applications. The in vitro treatment of neat EVA and EVA nanocomposites was performed by immersing the materials in oxidizing and hydrolytic agents, at a temperature of 37 째C, for 4 weeks. The in vitro mechanical properties of the materials under these environmentally challenging conditions were assessed. Based on morphology studies, the degree of MMT dispersion and exfoliation decreased as the nanofiller loading increased. The EVA containing 1 wt% organo-MMT exhibited the best nanofiller dispersion and exfoliation characteristics. The surface degradation features of this nanocomposite were seen to be smoother than those of neat EVA and other EVA nanocomposites. Furthermore, the EVA nanocomposites have improved mechanical properties in comparison with the neat EVA, and these properties were less affected by the in vitro conditions. The best in vitro mechanical properties were achieved when 1 wt% of organo-MMT was added into the EVA. It was postulated that the presence of a better dispersed and exfoliated organo-MMT layered structure introduced a more tortuous path for the diffusion of oxidants and water molecules, thereby decreasing their permeation towards the EVA molecular chains. Therefore, the degradation kinetics within the EVA molecular chains were at a lower rate, which resulted in enhanced biostability. Furthermore, the toughness of the hydrated EVA (exposed to PBS at 37 째C) was greatly enhanced with the addition of the 1 wt% organo-MMT. The biocompatibility assessment suggests that the EVA nanocomposites are not cytotoxic, and thus have fulfilled the prerequisite to be further developed as a biomedical material.