Background <p>Malignant pleural mesothelioma is a rare disease with a poor prognosis; distinguishing it from non-specific pleurisy is essential for determining an appropriate treatment strategy. We aimed to evaluate the diagnostic utility and safety of full-thickness biopsy performed during semi-rigid pleuroscopy under local anaesthesia to differentiate between malignant pleural mesothelioma and non-specific pleurisy.</p> Methods <p>Consecutive patients who attempted full-thickness biopsy using a cryoprobe or an insulated-tip diathermic knife during semi-rigid pleuroscopy between April 2019 and October 2023 were retrospectively enrolled. The diagnostic utility of full-thickness biopsy for distinguishing malignant pleural mesothelioma from non-specific pleurisy was assessed based on diagnostic accuracy, specimen quality, and procedural safety.</p> Results <p>Among the 64 patients who underwent full-thickness biopsy, 28 diagnosed with malignant pleural mesothelioma or non-specific pleurisy were included in this study. With the exception of one malignant pleural mesothelioma case diagnosed by surgical biopsy, 13 malignant pleural mesothelioma and 14 non-specific pleurisy cases were histologically diagnosed through full-thickness biopsy, with clinical courses supporting these diagnoses. The median full-thickness biopsy specimen size was 18.8&#xa0;mm² (range: 0.6-364.2 mm²), and in 25 cases (89.3%), full-thickness pleura was pathologically confirmed. Full-thickness biopsy demonstrated a sensitivity of 92.9%, specificity of 100%, positive predictive value of 100%, negative predictive value of 93.3%, and an overall diagnostic accuracy of 96.4%. No severe complications were reported with the procedures.</p> Conclusion <p>Full-thickness biopsy during semi-rigid pleuroscopy provides high diagnostic accuracy and safety for differentiating malignant pleural mesothelioma from non-specific pleurisy, while yielding high-quality pleural tissue specimens.</p>