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RATIONALE AND OBJECTIVES Biopsy of lung nodules in the lower lung fields can be difficult because of breathing motion. Ipsilateral phrenic nerve block (PNB) before biopsy should make the biopsy safer, easier, and more precisely targeted. We describe the use of ultrasound-guided PNB before lung nodule biopsy, including relevant anatomy and variations, complications, and technique, along with our first 40 cases. MATERIALS AND METHODS We retrospectively reviewed patients who underwent PNB before computed tomography (CT)- or ultrasound-guided lung nodule biopsy from April 2015 through March 2020. Patient demographics, CT fluoroscopy time, radiation dose, complications, diagnostic yield, and effectiveness of PNB were recorded. Effectiveness of PNB was based on direct observation of diaphragmatic motion. Control group data for biopsies during the same time frame were collected and matched with nodules ≤1 cm from the PNB group. RESULTS Among 40 patients identified, no complications occurred related to the PNB. Mean (SD) nodule size was 12.4 (6.2) mm. True-positive results were obtained in 39 patients (98%), with 1 false-negative after an ineffective PNB. PNB was effective in 70%. When CT fluoroscopy was used for the biopsy, radiation dose was significantly lower after an effective PNB than an ineffective PNB (p < .001). Effective PNB was significantly more common with injection of ≥4 mL of local anesthetic (p = .01). Comparison with 19 matched controls showed significantly fewer instances of pneumothorax (p = .02) and greater diagnostic success (p = .03) for the PNB group. CONCLUSION Ultrasound-guided PNB is safe and effective and can improve outcomes when used before lung nodule biopsy.