We have identified two genes in the genomic database for Caenorhabditis elegans that code for proteins with significant sequence similarity to the mammalian soluble epoxide hydrolase (sEH). The respective transcripts were cloned from a mixed stage cDNA library from C. elegans. The corresponding proteins obtained after recombinant expression in insect cells hydrolyzed standard epoxide hydrolase substrates, including epoxyeicosatrienoic acids (EETs) and leukotoxins (EpOMEs). The enzyme activity was inhibited by urea-based compounds originally designed to inhibit the mammalian sEH. In vivo inhibition of the enzymes using the most potent of these compounds resulted in elevated levels of the EpOMEs in the nematode. These results suggest that the hydrolases are involved in the metabolism of possible lipid signaling molecules in C. elegans.