Radiofrequency discharge of helium gas at low pressure was employed to modify surface properties of polycarbonate. The effects of process parameters on wettability and plasma etching were determined by monitoring surface energy and weight loss, respectively. Quadratic equations for surface energy and weight loss, in terms of process variables, namely power, pressure, flowrate and treatment time were developed. Multiple response optimization was performed using central composite design (CCD) of response surface methodology (RSM) to maximize the surface energy and minimize the weight loss. Helium plasma treated polycarbonate resulted in increased hydrophilicity. From optical emission spectroscopic studies helium was identified as excited and metastable atom and ions which caused surface chemistry and morphology changes. Enhanced biocompatibility in terms of increased cell adhesion and proliferation was observed for all plasma treatment conditions. Confluent cell growth was observed with helium plasma treated polycarbonate. Both reduced platelet adhesion and increased partial thromboplastin time (increased to 204 s from 128 s corresponding to untreated polycarbonate) confirm the improved blood compatibility of plasma treated polycarbonate. © 2011 by Taylor & Francis Group, LLC.