EUS-guided radiofrequency ablation (EUS-RFA) has been increasingly used for the treatment of pancreatic neoplasms. The role of EUS-RFA in the management of pancreatic cancer has not yet been elucidated. This study aimed to evaluate the survival impact of EUS-RFA in unresectable pancreatic cancer.Twenty-two patients (n = 14, locally advanced unresectable; n = 8, metastatic) with unresectable pancreatic cancer underwent EUS-RFA combined with subsequent chemotherapy between May 2016 and June 2019. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were evaluated.EUS-RFA was successful in all patients. The median number of RFA sessions was 5 (interquartile range, [IQR], 3.25-5.75). After successful EUS-RFA, subsequent gemcitabine-based chemotherapy was performed. Early procedure-related adverse events occurred in 4 out of 107 sessions (3.74%), including peritonitis (n = 1) and abdominal pain (n = 3). During follow-up over a median of 21.23 months (IQR, 10.73-27.1), the median OS and PFS were 24.03 months (95% confidence interval [CI], 16-35.8) and 16.37 months (95% CI, 8.87-19), respectively.EUS-RFA is technically feasible and safe for the management of unresectable pancreatic cancer. EUS-RFA combined with systemic chemotherapy may be associated with favorable survival outcomes. Further larger-scale prospective comparative study is required to confirm these findings.