Objective:The aim of this study was to retrospectively assess the effect of comprehensive cryosurgery (ablation of intrapancreatic and extrapancreatic tumors) plus immunotherapy in metastatic pancreatic cancer. Methods:We divided 106 patients (57 men, 49 women; median age, 65 years) into the cryoimmunotherapy (31 patients), cryotherapy (36 patients), immunotherapy (17 patients), and chemotherapy groups (22 patients). Pretreatment immune function was tested in patients who underwent immunotherapy. Overall survival (OS) after diagnosis of metastatic pancreatic cancer was assessed after a 4-year follow-up. Results:Median OS was higher in the cryoimmunotherapy (13 months) and cryotherapy groups (7 months) than in the chemotherapy group (3.5 months; both P < 0.001) and was higher in the cryoimmunotherapy group than in the cryotherapy (P < 0.05) and immunotherapy groups (5 months; P < 0.001). In both the cryoimmunotherapy and cryotherapy groups, median OS was higher after multiple cryoablations than after a single cryoablation (P = 0.0048 and 0.041, respectively). In both groups, the median OS was higher in patients with normal immunologic function than in those with immune dysfunction (P < 0.0001 and P = 0.0004, respectively). Conclusions:Cryoimmunotherapy significantly increased OS in metastatic pancreatic cancer. Multiple cryoablations and normal pretreatment immunologic function were associated with better prognosis.