Diethylcarbamazine (DEC) has been used to treat lymphatic filariasis in tropical countries since the 1940s. Its mode of action is still unclear, with several reports suggesting a host immune system-mediated mechanism. We previously demonstrated that DEC causes transient spastic paralysis in the filarial nematode Brugia malayi due to the activation of TRP-2. Here we show that DEC causes transient paralysis in C. elegans at high concentrations and is 200x less potent compared to its effect on B. malayi. C. elegans trp-2(sy691) mutants are like the wild-type and only paralyzed by high concentrations of DEC. Our results demonstrate that high concentrations of DEC cause paralysis of C. elegans independent of TRP-2.