| Summary: | This systematic review and meta-analysis evaluate the comparative diagnostic efficacy and safety of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transbronchial mediastinal cryobiopsy (EBUS-TBMC) for sampling mediastinal and hilar lymph nodes. Following the PRISMA 2020 guidelines, 20 studies published between January 2020 and July 2025 were analysed to provide a comprehensive performance overview. The results demonstrate that EBUS-TBMC offers a significantly higher overall diagnostic efficacy compared to EBUS-TBNA, with a pooled risk difference (RD) of 0.30 (95% CI: 0.17–0.44, <i>p</i> < 0.001). The subgroup analyses revealed a trend toward a superior yield for EBUS-TBMC in lymphoma (RD 0.11, <i>p</i> = 0.05) and sarcoidosis (RD 0.03, <i>p</i> = 0.077), while no significant differences were found for lung cancer subtypes. Safety profiles remained comparable, with no significant differences in the risk of pneumothorax (RD 0.00, <i>p</i> = 1.00) or bleeding (RD 0.00, <i>p</i> = 0.965). In conclusion, these findings support integrating EBUS-TBMC into diagnostic algorithms when preserved tissue architecture is critical, such as for lymphoproliferative disorders, granulomatous diseases, and advanced molecular profiling, providing a safe and more effective alternative to conventional needle aspiration.
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