The polarized trafficking of axonal and dendritic components is essential for the development and maintenance of neuronal structure and function. Neuropeptide-containing dense-core (DCVs) vesicles are trafficked in a polarized manner from the cell body to their sites of release; however, the molecules involved in this process are not well defined. Here we show that the scaffolding protein SYD-2/Liprin-α is required for the normal polarized localization of Venus-tagged neuropeptides to axons of cholinergic motor neurons in C. elegans. In syd-2 loss of function mutants, the normal polarized localization of INS-22 neuropeptide-containing DCVs in motor neurons is disrupted, and DCVs accumulate in the cell body and dendrites. Time-lapse microscopy and kymograph analysis of mobile DCVs revealed that syd-2 mutants exhibit decreased numbers of DCVs moving in both anterograde and retrograde directions, and a corresponding increase in stationary DCVs in both axon commissures and dendrites. In addition, DCV run lengths and velocities were decreased in both axon commissures and dendrites of syd-2 mutants. This study shows that SYD-2 promotes bi-directional mobility of DCVs and identifies SYD-2 as a novel regulator of DCV trafficking and polarized distribution.