Transesophageal EUS-FNA have become a useful tool in the evaluation of the mediastinum, especially during the staging work-up examination of patients with non-small-cell lung cancer (NSCLC) or other malignancies. We report a challenging case of a 53 years-old woman with an endometrial adenocarcinoma who subsequently presented with right pleural effusion, diffuse pleural thickening with few pleural lesions. The patient referred a long history of exposure to amiantum, this posing a differential diagnosis between primary pleural tumour (mesothelioma) and neoplastic pleural localization of the endometrial cancer. The cytological examination of the pleural effusion (sampled via thoracenthesis) was not adequate to reach a diagnosis. Although a right-video-assisted thoracoscopy was considered the gold standard in this clinical setting to achieve a tissue acquisition of the pleura, an EUS (as the least invasive procedure) was attempted to reach a definitive diagnosis. EUS-FNTA of the pleura was done using a 19-Gauge needle and the pathological and immunophenotypic features were diagnostic for a pleural metastasis of high-grade endometrial serous carcinoma. The patient received adjuvant chemotherapy with a complete regression of the pleural lesions. We take the opportunity of this challenging case to discuss the efficacy and safety of EUS-FNAT to sample the pleural lesions with the use of a large calibre needle if the lesion lies just under the EUS cursor. We may assume that, in selected patients, this technique could be presented as a viable option to the more invasive surgical procedure, which has been previously the gold standard for the pleural tissue acquisition.