Background: The heritage of occupational and environmental asbestos exposure in Piedmont, Italy, is an enduring epidemic of malignant pleural mesothelioma (MPM). Pleural biopsy (PB) performed via thoracoscopy (or video-assisted thoracic surgery (VATS)) remains the diagnostic gold standard for patients with suspected mesothelioma. The aim of our study was to investigate the accuracy of PB via VATS and to analyze the diagnostic path of the patients who experienced an initial MPM misdiagnosis. Method: Patients who underwent PB by VATS for suspected MPM from 2004 to 2013 were analyzed. The Registry of Malignant Mesothelioma (RMM) records were examined to crosscheck incident cases and to recognize misdiagnosed MPM. Sensitivity and specificity of the initial PB assessment versus the final classification of cases by RMM were evaluated. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test.Result: Data of 552 patients were analyzed. Of those, MPM was diagnosed in 178 cases (32%) and no false-positive PBs were observed. Sensitivity and specificity were 93% and 100%, respectively. The number of false-negative PBs was 14 (2%). Of those, 10 (71%) had an initial diagnosis of chronic pleuritis, 3 (28.5%) of atypical mesothelial proliferation and 1 had reactive mesothelial proliferation. All of them reported a history of asbestos exposure and the correct diagnosis was reached after a median of 160 days (interquartile range 86-243) as follow: 9 (64%) after a further PB by VATS, 3 (22%) by cytology examination of a pleural effusion, 1 (7%) by fine-needle biopsy and 1 (7%) by open surgery. The median survival time of the patients with eventual MPM diagnosis was 13.8 months (CI 95%: 10.3-16.6).). Oneand 4-year survival were 52% and 10% in MPM PB positive cases and 50% and 19% in false-negative cases (P¼0.66) (Figure 1). Conclusion: When a history of asbestos exposure is reported and a strong clinical suspicion persists after a negative PB, iterative biopsy attempts should be considered. In high-volume centers, MPM misdiagnosis rate remains small and future advancement in diagnostic technologies could further increase the accuracy of diagnosis.