Despite attempts to use multiple drug combinations that include gemcitabine (GEM), there is very little evidence that these combination regimens are superior to the single use of this agent. We therefore investigated the suppressive effect of the combination of systemically administered GEM and locally administered interleukin-2 (IL-2) on liver metastasis in pancreatic cancer. Tumor-bearing mice were randomly divided into four groups: a control group, an IL-2 intrasplenic (is) administration group, a GEM intraperitoneal (ip) administration group, and a GEM ip+IL-2 is group. Liver weight, liver metastases, and tumor diameter (as assessed by the Winn assay) were compared among groups. Liver weight was significantly lower in the GEM+IL-2 group than in the control and IL-2 groups. The number of liver metastases was significantly reduced in the GEM+IL-2 group compared with all other groups. Splenocyte production of interferon-gamma increased significantly in the GEM+IL-2 group after stimulation with Concanavalin A. Furthermore, tumor diameter was significantly reduced in the GEM+IL-2 group in the Winn assay when compared to that of the control group. These findings suggest that a combined regimen of GEM and portally administrated IL-2 might prevent liver metastasis in pancreatic cancer patients more effectively than current approaches and could prove useful as a postsurgical adjuvant therapeutic.