Physicians increasingly use transthoracic ultrasound (US) as an aid for diagnostic procedures. At the bedside, US helps to visualize neoplasms in the chest wall, pleura, peripheral lung, and anterior mediastinum involving or abutting the pleura. Histology specimens from cutting-needle biopsies have been shown to be safe and effective. This prospective study determined the yield and safety of US-guided fine-needle aspiration biopsy (FNAB) as a first-line bedside investigation. We recruited 97 consecutive patients, and of these, 85 underwent both cutting-needle biopsy and FNAB. These were adequate for diagnosis in 81.2% and 80% of cases, respectively, with a combined yield of 90%. Measured with a novel semiquantitative score, FNAB allowed a diagnosis with fewer special investigations than cutting biopsy. US-guided FNAB by pulmonologists performed best in lung carcinoma and can be recommended as a first-line investigation in patients with a high clinical suspicion of this diagnosis.