Heritable variation in behavioural traits generally has a complex genetic basis(1), and thus naturally occurring polymorphisms that influence behaviour have been defined only in rare instances(2,3). The isolation of wild strains of Caenorhabditis elegans has facilitated the study of natural genetic variation in this species(4) and provided insights into its diverse microbial ecology(5). C. elegans responds to bacterial infection with conserved innate immune responses(6-8) and, although lacking the immunological memory of vertebrate adaptive immunity, shows an aversive learning response to pathogenic bacteria(9). Here, we report the molecular characterization of naturally occurring coding polymorphisms in a C. elegans gene encoding a conserved HECT domain-containing E3 ubiquitin ligase, HECW-1. We show that two distinct polymorphisms in neighbouring residues of HECW-1 each affect C. elegans behavioural avoidance of a lawn of Pseudomonas aeruginosa. Neuron-specific rescue and ablation experiments and genetic interaction analysis indicate that HECW-1 functions in a pair of sensory neurons to inhibit P. aeruginosa lawn avoidance behaviour through inhibition of the neuropeptide receptor NPR-1 (ref. 10), which we have previously shown promotes P. aeruginosa lawn avoidance behaviour(11). Our data establish a molecular basis for natural variation in a C. elegans behaviour that may undergo adaptive changes in response to microbial pathogens.