Background <p>Preoperative CT-guided percutaneous localization of pulmonary nodules is widely used in clinical practice but is often associated with localization-related complications. Intraoperative titanium clip localization may provide a safer localization strategy. This study aimed to compare the effectiveness and safety of these two approaches.</p> Methods <p>This single-center prospective cohort study included 189 patients who underwent pulmonary nodule resection after localization between October 2023 and November 2025. Patients were divided into an intraoperative titanium clip localization group (<i>n</i> = 123) and a preoperative medical glue localization group (<i>n</i> = 66) based on the localization method. Localization success rate, localization-related complications, and perioperative outcomes were analyzed.</p> Results <p>A total of 252 pulmonary nodules were localized. The intraoperative group demonstrated a significantly higher localization success rate than the preoperative group (99.4% vs. 89.0%; OR, 18.07; 95% CI, 2.18–149.84; <i>P</i> = 0.007), along with a lower incidence of localization-related complications (0% vs. 30.3%; OR, 0.004). However, the duration of general anesthesia was longer in the intraoperative group (196.34 ± 54.46 vs. 162.76 ± 57.19&#xa0;min; <i>P</i> = 0.001). There were no significant differences in postoperative drainage volume, postoperative complication rates, or length of hospital stay between the two groups.</p> Conclusions <p>Intraoperative titanium clip localization demonstrated a higher localization success rate and a lower incidence of localization-related complications. It may have potential value for simultaneous localization of multiple pulmonary nodules. However, this approach was associated with a longer duration of general anesthesia.</p>