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Confocal laser endomicroscopy (CLE) has evolved to allow in vivo real-time biopsy for the classification of colorectal lesions.The primary aim of this study was to assess the effectiveness of CLE for discriminating colorectal neoplasms from non-neoplasms and its contributing factors. The secondary aim was to compare the efficacy of endomicroscopy and chromoendoscopy for diagnosing colorectal neoplasms.A systematic review of the literature published between 2000 and 2012 was conducted. Pooled sensitivity and specificity were compared using univariate regression analysis according to prespecified subgroups. Pooled relative risk was computed to compare the accuracy of endomicroscopy and chromoendoscopy.Fifteen studies involving 719 patients and 2290 specimens were analysed. The pooled sensitivity of all studies was 0.94 [95% confidence intervals (CI): 0.88–0.97], and pooled specificity was 0.95 (95% CI: 0.89–0.97). Real-time CLE yielded higher sensitivity (0.96 vs 0.85, P < 0.001) and specificity (0.97 vs 0.82, P < 0.001) than blinded CLE. For real-time CLE, endoscopy-based systems had better sensitivity (0.96 vs 0.89, P < 0.001) and specificity (0.99 vs 0.82, P < 0.0001) than probe-based systems. CLE yielded equivalent accuracy compared with magnifying virtual chromoendoscopy and magnifying pigment chromoendoscopy (P > 0.05).CLE is comparable to colonoscopic histopathology in diagnosing colorectal neoplasms, and is better in conjunction with conventional endoscopy. An endoscopy-based rather than a probe-based modality would be optimal in the application of CLE.