In this study, amphiphilic polyoxanorbornene with different quaternary alkyl pyridinium side chains were synthesized. The biological efficiencies of these polymers, with various alkyl substituents, were determined by bacterial growth inhibition assays and hemolytic activity (HC(50)) against human red blood cells (RBCs) to provide selectivity of these polymers for bacterial over mammalian cells. A series of polymers with different alkyl substituents (ethyl, butyl, hexyl, octyl, decyl and phenylethyl) and two different molecular weights (3 and 10 kDa) were prepared. The impact of alkyl chain length divided the biological activity into two different cases: those with an alkyl substituent containing four or fewer carbons had a minimum inhibitory concentration (MIC) of 200 mu g . mL(-1) and a HC(50) greater than 1650 mu g . mL(-1), while those with six or more carbons had lower MICs <= 12.5 mu g . mL(-1) and HC(50) < 250 mu g . mL(-1). Using MSI-78, the potent Magainin derivative which has an MIC = 12.0 mu g . mL(-1) and HC(50) = 120 mu g . mL(-1), as a comparison, the polymers with alkyl substituents <= C(4) (four carbons) were not very potent, but did show selectivity values greater than or equal to MSI-78. In contrast, those with alkyl substituents >= C6 were as potent, or more potent, than MSI-78 and in three specific cases demonstrated selectivity values similar to, or better than, MSI-78. To understand if these polymers were membrane active, polymer induced lipid membrane disruption activities were evaluated by dye leakage experiments. Lipid composition and polymer hydrophobicity were found to be important factors for dye release.