Synthetic polymeric antimicrobials have received enormous attention recently on the back of increasing multidrug-resistance microbes. While conventional small molecular antibiotics act on specific targets to inhibit microbe activities, macromolecular antimicrobials physically destroy cell membranes of the organism rendering them ineffective; the mechanism of the latter aids in the prevention of developing drug-resistance microbes. In this investigation, we report on the synthesis of biodegradable cationic polycarbonates containing propyl and hexyl side chains quaternized with various nitrogen-containing heterocycles, such as imidazoles and pyridines, and their in vitro antimicrobial application. These polymers demonstrate a wide spectrum of activity (using minimum inhibitory concentrations analysis) against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus). Hemolysis experiments also show high selectivity toward the tested microbes over mammalian (rat) red blood cells (rRBCs). In particular, some of the polymers can achieve >250 times selectivity of S. aureus over rRBCs. In addition, the polymers function via a membrane-lytic mechanism; hence, they are less likely to develop drug resistance. All these properties make them ideal candidates as antimicrobial agents. © 2014 American Chemical Society.