Pseudomonas aeruginosa is a Gram-negative bacterium which exacts a heavy burden on immunocompromised patients, but is non-pathogenic in a healthy host. Using small signaling molecules called acyl-homoserine lactones (AHLs), populations of P. aeruginosa can coordinate phenotypic changes, including biofilm formation and virulence factor secretion. This concentration-dependent process is called quorum sensing (QS). Interference with QS has been identified as a potential source of new treatments for P. aeruginosa infection. The human enzyme paraoxonase 1 (PON1) degrades AHL molecules, and is a promising candidate for QS interference therapy. Although paraoxonase orthologs exist in many species, genetic redundancy in humans and other mammals has made studying the specific effects of PON1 quite difficult. Arthropods, however, do not express any PON homologs. We generated a novel model to study the specific effects of PON1 by transgenically expressing human PON1 in Drosophila melanogaster. Using this model, we showed that P. aeruginosa infection lethality is QS-dependent, and that expression of PON1 has a protective effect. This work demonstrates the value of a D. melanogaster model for investigating the specific functions of members of the paraoxonase family in vivo, and suggests that PON1 plays a role in innate immunity.