This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy.<b>Experimental Design:</b> Consecutive patients (<i>n</i> = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care.<b>Results:</b> DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; <i>P</i> < 0.001).