Title: Diagnostic Breast Imaging Performance in Pregnant and Lactating Patients Purpose: This study aimed to retrospectively assess the diagnostic accuracy of combined mammography and ultrasound (MG+US) in pregnant and lactating women, utilizing the largest sample size to date. Materials and Methods: A retrospective chart review from January 2013 to June 2024 included pregnant or lactating women who underwent breast imaging at UW Health. Imaging results were classified as true positive, false positive, true negative, or false negative. Reference standards included biopsy or ≥2 years of follow-up for benign cases. The primary outcomes were sensitivity and specificity of MG+US. BI-RADS 3 (probably benign) rates, follow-up adherence, and comparison of BI-RADS 3 utilization between ultrasound alone and MG+US were analyzed using a Z-test for two proportions. Results: Of 1,000 patients, 756 were lactating and 251 were pregnant, and 7 received additional postpartum imaging. Of the 497 mammograms performed, 57.1% showed extremely dense tissue. The most common symptom prompting imaging was a palpable lump. Fourteen patients were diagnosed with pregnancy-associated breast cancer (PABC), with 13 initially categorized as BI-RADS 4 or 5 by MG+US and 1 by ultrasound alone. BI-RADS 3 recommendation rates were 14% in pregnant patients (71% follow-up adherence) and 12% in lactating patients (62% follow-up adherence). Diagnostic MG+US had 100% sensitivity (13/13), 85% specificity (308/363), 19% positive predictive value (13/63), and 100% negative predictive value (308/308). Conclusion: Our study demonstrates that diagnostic breast imaging in pregnant and lactating women is effective and accurate in detecting PABC and should not be delayed. Reduced BI-RADS 3 utilization rates when MG+US is used, compared to ultrasound alone, highlights the added value of mammography in providing a more comprehensive and efficient diagnostic strategy in this patient population. EMR patient reports revealed persistent hesitancy among patients and clinicians about using diagnostic mammography during pregnancy, highlighting the need for clearer communication about its safety. This study contributes to breast imaging research by underscoring the importance of evidence-based imaging algorithms, thereby improving outcomes for pregnant and lactating patients. Clinical Relevance: The reduction in BI-RADS 3 utilization with combined mammography and ultrasound helps minimize unnecessary follow-ups and alleviates patient anxiety in pregnant and lactating women. Although combined imaging modalities are generally not recommended for women under 30, revisiting diagnostic imaging protocols for this special population could enhance diagnostic accuracy and improve patient outcomes. Promoting education on safe, evidence-based imaging practices is essential for better management of breast concerns in these patients.