Cationic and amphiphilic polymers are known to exert broad-spectrum antibacterial activity by a putative mechanism of membrane disruption. Typically, nonspecific binding to hydrophobic components of the complex biological milieu, such as globular proteins, is considered a deterrent to the successful application of such polymers. To evaluate the extent to which serum deactivates antibacterial polymethacrylates, we compared their minimum inhibitory concentrations in the presence and absence of fetal bovine serum. Surprisingly, we discovered that the addition of fetal bovine serum (FBS) to the assay media in fact enhances the antimicrobial activity of polymers against Gram-positive bacteria S. aureus, whereas the opposite is the case for Gram-negative E. coli. Here, we present these unexpected trends and develop a hypothesis to potentially explain this unusual phenomenon.