Rabphilin, a putative rab effector, interacts specifically with the GTP-bound form of the synaptic vesicle-associated protein rab3A. In this study, we define in vivo functions for rabphilin through the characterization of mutants that disrupt the C. elegans rabphilin homolog. The mutants do not display the general synaptic defects associated with rab3 lesions as assayed at the pharmacological, physiological and ultrastructural level. However, rabphilin mutants exhibit severe lethargy in absence of mechanical stimulation. Furthermore, rabphilin mutations display strong synergistic interactions with hypomorphic lesions in the syntaxin, SNAP-25 and synaptobrevin SNARE genes; double mutants were non-responsive to mechanical stimulation. These synergistic interactions were independent of rab3 function and not observed in rab3 SNARE double mutants. Our data reveal rab3 independent functions for rabphilin in the potentiation of SNARE function.