Abstract Background: Selecting the most effective guidance method for peripheral lung biopsy is a priority for interventional radiologists. The clinical trials comparing efficacy and safety of ultrasound (US) and computerized tomography (CT) as biopsy-guiding modalities for peripheral lung biopsy tech-niques are limited in the literature, and most of them are retrospective. Aim of Study: To compare the efficacy and safety of biopsy guided by US versus CT for lung lesions with pleural contact. Patients and Methods: This is a prospective comparative study; included 40 patients underwent image-guided biopsy at Nasser Institute Hospital, Cairo, Egypt. From June 2018 to May 2020. Lesion size, location, length of pleural contact, number of needle passes, and number of tissues cores, proce-dure times, complications, and histopathology reports were documented for each biopsy. Statistical analysis using Fisher's exact test and t-test, (Alfa-point=0.05). Results: US-guided group had significantly fewer com-plications; 15% (3/20) versus 40% (8/20) for CT-guided group; (p=0.036). Fewer number of needles passes were required for US-guided biopsies (mean, 2.7 passes ±0.8 (SD) than for CT-guided biopsies (mean, 3.4 passes ±1.2 (SD); p=0.04). Proce-dural times were significantly shorter in the US-guidance group, with a mean procedure time of 6.3 minutes ±2.2 (SD) compared to 21.8 minutes ±5.7 (SD) for CT-guided biopsies; (p=0.0001). Conclusion: US guidance should be thought of as a primary tool for guidance of peripheral lung lesions' biopsy, because it is superior to CT in safety and time-saving with comparable accuracy.