Simple SummaryRecurrences after primary resection of pancreatic cancer are generally treated with chemotherapy or best supportive care. Despite some reports of encouraging results after the re-resection of recurrences, the real role of surgery in this setting remains unclear. The aim of our systematic review and meta-analysis was to define the benefit of surgery in the case of isolated local recurrence. The data collected on 431 patients suggest an overall survival benefit of 29 months for patients re-operated compared to patients given medical therapies. In selected patients with recurrent pancreatic cancer, resection is safe and feasible, and may offer a survival advantage.Purpose: To perform a systematic review and meta-analysis on the outcome of surgical treatment for isolated local recurrence of pancreatic cancer. Methods: A systematic review and meta-analysis based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was conducted in PubMed, Scopus, and Web of Science. Results: Six studies concerning 431 patients with recurrent pancreatic cancer met the inclusion criteria and were included in the analysis: 176 underwent redo surgery, and 255 received non-surgical treatments. Overall survival and post-recurrence survival were significantly longer in the re-resected group (ratio of means (ROM) 1.99; 95% confidence interval (CI), 1.54–2.56, I2 = 75.89%, p = 0.006, and ROM = 2.05; 95% CI, 1.48–2.83, I2 = 76.39%, p = 0.002, respectively) with a median overall survival benefit of 28.7 months (mean difference (MD) 28.7; 95% CI, 10.3–47.0, I2 = 89.27%, p < 0.001) and median survival benefit of 15.2 months after re-resection (MD 15.2; 95% CI, 8.6–21.8, I2 = 58.22%, p = 0.048). Conclusion: Resection of isolated pancreatic cancer recurrences is safe and feasible and may offer a survival benefit. Selection of patients and assessment of time and site of recurrence are mandatory.