The dense core vesicle (DCV) is a key organelle involved in the secretion of hormones and neuropeptides in endocrine cells and neurons in response to stimulation. However, the mechanisms underlying its biogenesis, trafficking and exocytosis remain largely unknown. In this study, to discover novel players functioning in DCV secretion, we performed a genome-wide RNAi screen in C. elegans by observing worm defecation behavior. A series of genes that function in the intestine to regulate DCV biogenesis or exocytosis were successfully identified, including CAB-1, which was further determined to be a specific regulator for DCV exocytosis. In the intestine, cab-1 mutation causes reduced secretion of intestinal DCV cargoes. In the nervous system, the loss of CAB-1 leads to the accumulation of DCV markers in the presynaptic region, but synaptic vesicles are not affected. This work demonstrates that CAB-1 is a regulatory factor specifically involved in DCV secretion.