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Simple Summary: Pancreatic cystic lesions are diagnosed with an increasing frequency, thus comprising a significant routine condition in clinical practice. In addition to the current approaches, which include surgery and surveillance, endoscopic ultrasound (EUS) provides the potential of an additional therapeutic tool. This review collected the existing literature regarding EUS-guided ablation techniques for pancreatic cystic lesions and assessed its efficacy and safety. The cumulative effect in treating pancreatic cysts was 44% (95%CI: 31–57), with the highest rate achieved when a combination of ethanol and paclitaxel was injected into the cysts (70%; 95%CI: 64–76). Considering safety, most adverse events were mild and occurred after ethanol injection. EUS-guided pancreatic cyst ablation seems to be an acceptable and safe procedure, with promising results in appropriately selected patients. Background: Pancreatic cystic lesions (PCL) represent an increasingly diagnosed condition with significant burden to patients' lives and medical resources. Endoscopic ultrasound (EUS) ablation techniques have been utilized to treat focal pancreatic lesions. This systematic review with meta-analysis aims to assess the efficacy of EUS ablation on PCL in terms of complete or partial response and safety. Methods: A systematic search in Medline, Cochrane and Scopus databases was performed in April 2023 for studies assessing the performance of the various EUS ablation techniques. The primary outcome was complete cyst resolution, defined as cyst disappearance in follow-up imaging. Secondary outcomes included partial resolution (reduction in PCL size), and adverse events rate. A subgroup analysis was planned to evaluate the impact of the available ablation techniques (ethanol, ethanol/paclitaxel, radiofrequency ablation (RFA), and lauromacrogol) on the results. Meta-analyses using a random effects model were conducted and the results were reported as percentages with 95% confidence intervals (95%CI). Results: Fifteen studies (840 patients) were eligible for analysis. Complete cyst resolution after EUS ablation was achieved in 44% of cases (95%CI: 31–57; 352/767; I2 = 93.7%), and the respective partial response rate was 30% (95%CI: 20–39; 206/767; I2 = 86.1%). Adverse events were recorded in 14% (95%CI: 8–20; 164/840; I2 = 87.2%) of cases, rated as mild in 10% (95%CI: 5–15; 128/840; I2 = 86.7%), and severe in 4% (95%CI: 3–5; 36/840; I2 = 0%). The subgroup analysis for the primary outcome revealed rates of 70% (95%CI: 64–76; I2 = 42.3%) for ethanol/paclitaxel, 44% (95%CI: 33–54; I2= 0%) for lauromacrogol, 32% (95%CI: 27–36; I2 = 88.4%) for ethanol, and 13% (95%CI: 4–22; I2 = 95.8%) for RFA. Considering adverse events, the ethanol-based subgroup rated the highest percentage (16%; 95%CI: 13–20; I2 = 91.0%). Conclusion: EUS ablation of pancreatic cysts provides acceptable rates of complete resolution and a low incidence of severe adverse events, with chemoablative agents yielding higher performance rates. [ABSTRACT FROM AUTHOR]