We recently determined that synuclein-gamma (SNCG) is highly expressed in human gallbladder cancer (GBC), and its abnormal expression is associated with tumor aggressiveness. To investigate the effects of SNCG gene silencing on the tumorigenic profiles of the GBC cell line, NOZ, short-hairpin RNA (shRNA) interference was employed. Specifically, the SNCG transcript was targeted by SNCG-shRNA lentiviral particles designed to silence SNCG gene expression. Following selection of NOZ cells stably expressing SNCG-shRNA, SNCG expression was examined by western blot and semi-quantitative RT-PCR analyses. Phenotypic hallmarks of gallbladder carcinogenesis were assayed by CCK-8, soft agar (colony formation), modified Boyden-Chamber (invasion), and flow cytometry (cell-cycle and apoptosis) assays. Our results showed that SNCG gene silencing in NOZ cells inhibited cell growth, colony formation, and invasion. In addition, it directly increased the effectiveness of paclitaxel in inducing G2/M cell-cycle arrest and cell apoptosis. Data from our in vivo study showed a decrease in tumor growth and weight in mice injected with SNCG-silenced NOZ cells. Together, these findings suggest that SNCG plays an important role in the progression of GBC.