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BACKGROUND AND AIMS: Current modalities for lymph node staging in cancer can be limited. We sought to evaluate the feasibility of needle-based confocal laser endomicroscopy (nCLE) at the time of endoscopic ultrasound (EUS) and to describe the nCLE features that distinguish between benign, malignant, and inflammatory lymph nodes. METHODS: We collected data on 28 consecutive patients during EUS staging of malignancy or assessment of enlarged lymph nodes. Patients underwent nCLE at the time of EUS followed by fine needle biopsy. nCLE images were correlated with the patients' final histopathology. RESULTS: All 28 patients successfully underwent nCLE during EUS without adverse events. There were 17 cases of carcinoma, 4 lymphoid malignancies, and 7 benign lymph nodes. We characterized the various nCLE features of the lymph node capsule and cortex. Features of carcinoma, such as clusters of dark pleomorphic tumor cells, were identified and found to correlate well with the final pathology. Lymphoid malignancies often had enlarged follicles, but this was inconsistent. CONCLUSIONS: nCLE of lymph nodes at the time of EUS is feasible and appears to be safe. Dark pleomorphic cells were readily identified in all of the malignant lymph nodes and correlated with tumor cells seen on histology.