Abstract Objectives: To assess the diagnostic performance of ultrasound-guided fine-needle aspiration (USFNA) in nonpalpable breast lesions (NPBLs) in a multidisciplinary setting. Methods: In total, 2,601 NPBLs underwent USFNA by a radiologist-pathologist team. Gold-standard diagnosis was based on surgery, core-needle biopsy, or 1-year imaging follow-up. USFNA’s diagnostic performance was analyzed in different clinical and imaging subgroups. Results: USFNA’s sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were, respectively, 92.6% (95% confidence interval CI, 90.8%-94.2%), 96.8% (95% CI, 95.8%-97.6%), 94.8% (95% CI, 93.2%-96.1%), and 95.4% (95% CI, 94.3%-96.4%). The best PPV was achieved in Breast-Imaging Reporting and Data System (BI-RADS) categories 4C and 5 and the best NPV in BI-RADS categories 2, 3, and 4A and in patients younger than 50 years. The mitotic count, BI-RADS categories, associated palpable cancer, and age (<50 or ≥50 years) were statistically independent factors (P < .05) between USFNA’s false-negative and true-positive results. Conclusions: USFNA is a robust diagnostic procedure in NPBLs. Age and the BI-RADS category of the lesion are important factors determining its performance.