Background and aims Given the variable diagnostic yield of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration for pancreatic cystic lesions (PCLs), novel imaging techniques including needle-based confocal laser endomicroscopy (nCLE) have been devised. The aim of this study was to perform a structured systematic review and meta-analysis to evaluate the diagnostic performance and safety of nCLE for the diagnosis of PCLs. Methods Individualized search strategies were developed in accordance with PRISMA and MOOSE guidelines and meta-analysis analyzed according to the Cochrane Diagnostic Test Accuracy working group methodology. Measured outcomes included diagnostic characteristics and procedure-associated adverse events. A bivariate model was used to compute combined weighted sensitivity, specificity, positive/negative likelihood ratio (LR), diagnostic odds ratio, and summary receiver operating characteristic curve with corresponding 95% confidence intervals (CIs). Results Seven studies (n=324; mean age: 63.99±5.36 y; 52.47% female) were included. The pooled sensitivity, specificity, positive LR, and negative LR of nCLE was 85% (95% CI, 71-93; I=74.20%), 99% (95% CI, 90-100; I=72.60%), 78.66 (95% CI, 7.99-774.68; I=26.86%), and 0.15 (95% CI, 0.07-0.31; I=75.84%), respectively. Diagnostic accuracy as measured by summary receiver operating characteristic curve was 99% (95% CI, 98-100). The pooled diagnostic odds ratio was 534 (95% CI, 50-5664; I=58.00%). Postprocedure pancreatitis developed in 1% (95% CI, 0-3; I=5.64%) of cases. Conclusions On the basis of this meta-analysis, nCLE appears to be an effective and safe technique for the diagnostic evaluation of PCLs. Although moderate-to-high amounts of heterogeneity were present, our results demonstrated that nCLE has a diagnostic accuracy of 99% with a low rate of adverse events.