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We prospectively analyzed the diagnostic yield and safety of ultrasound (US)-guided transthoracic needle aspiration biopsy in the histologic diagnosis of 40 patients with superior vena cava (SVC) syndrome. During a 4-yr period, 40 patients with SVC obstruction were admitted to National Taiwan University Hospital. Of these patients 10 had histologic confirmation by sputum cytology (3 patients), fiberoptic bronchoscopy with biopsy (2 patients), or lymph node biopsy (5 patients) at admission. A total of 30 undiagnosed patients underwent real-time ultrasonographic (US) evaluation as well as color Doppler imaging. Patients with tumor detectable by US underwent US-guided transthoracic needle aspiration biopsy. Of the 30 patients who received US chest examination, 29 had widening of the upper mediastinal shadows in the chest radiographs. In 27 patients tumors were detected by chest US. After assessment of collateral vessels by color Doppler US, these 27 patients underwent US-guided transthoracic needle aspiration biopsies; histologic diagnoses were confirmed in 25. The diagnostic yield was 83.3%. The mean duration from admission to histologic diagnosis was 2.1 days. None of the patients developed complications. We conclude that chest US and color Doppler images are useful tools for evaluation of patients with SVC syndrome. US-guided transthoracic needle aspiration biopsy appears to be a safe, effective, and rapid approach for obtaining an accurate histologic diagnosis. Specific treatment can thus be initiated without delay.