High molecular weight poly(vinyl chloride) and aliphatic polyurethane (Tecoflex)-based ion selective membranes, with normal and reduced amounts of plasticizer, as well as without plasticizer, were tested with respect to their analytical properties, their biocompatibility, and cellular responses. The analytical properties of the membranes did not change significantly within a wide range of polymer to plasticizer ratios. However, the membranes with reduced plasticizer content had better adhesive properties, less anion interference, extended life time, and better biocompatibility. Using the cage implant system, the results showed that an increase of plasticizer weight percent in Tecoflex membranes correlated positively with the increase in host inflammatory response up to 14 days of implantation. The results also demonstrated that both PVC and Tecoflex-based ion-selective membranes with the most common membrane composition (1:2 polymer to plasticizer ratio) exhibited a similar acute inflammatory response, but the PVC-based membrane elicited a reduced chronic inflammatory response when compared with the Tecoflex-based membrane.