Objective <p>Myocardial biopsy plays a critical role in the diagnosis of myocardial disorders, particularly in cases with undetermined etiology. This study was designed to assess the feasibility and safety of a novel approach—ultrasound-guided trans-thoracic myocardial biopsy.</p> Methods <p>Fourteen patients underwent ultrasound-guided trans-thoracic biopsy for myocardial tissue sampling, with evaluation of potential complications. Among these patients, three were initially suspected of having cardiac amyloidosis (CA) based on the clinical evaluation, one was suspected of hypertrophic cardiomyopathy (HCM), one was referred for post-transplantation rejection monitoring, and one presented with a suspected cardiac tumor. The remaining eight cases were suspected to involve various types of cardiomyopathy or myocarditis.</p> Results <p>Myocardial tissue samples were obtained from 14 patients, yielding a total of 19 specimens. An average of 1.36 ± 0.6 samples was collected per patient, with a mean specimen length of 13.2 ± 5.2&#xa0;mm, which was adequate for histopathological assessment. Pericardial effusion occurred in two patients (14.2%), one of whom required percutaneous drainage, without progression to pericardial tamponade. No cases of nonsustained or sustained ventricular tachycardia, conduction disturbances, cardiac perforation, stroke, or pneumothorax were observed during the procedure or hospitalization. In all cases, the obtained myocardial specimens were sufficient for pathological evaluation.</p> Conclusion <p>This study demonstrates that ultrasound-guided trans-thoracic myocardial biopsy is a technically feasible procedure with acceptable preliminary safety in a small, highly selected patient cohort.</p>