© 2021 The Association of University RadiologistsRationale and Objective: We aimed to compare the diagnostic performance of an automated breast ultrasound system (ABUS) with handheld ultrasound (HHUS) in the detection and characterization of lesions regarding BI-RADS classification in women with dense breasts. Materials and Methods: After ethical approval, from July 2017 to August 2019, 592 consecutive patients were enrolled in this prospective study. On the same day, patients underwent ABUS followed by HHUS. Three breast radiologists participated in this study. The number and type of lesions and BI-RADS categorization of both ABUS and HHUS examinations of each patient were recorded in an excel file. The level of agreement between the two ultrasound systems in terms of lesion number and BI-RADS category were analyzed statistically. Results: ABUS and HHUS detected 1005 and 1491 cystic and 270 and 336 mass lesions in 592 patients respectively. ABUS and HHUS detected 171 and 167 positive/suspicious cases (BIRADS 0/3/4/5). Forty suspicious lesions underwent core needle biopsy whereas 11 malignant lesions were detected by both methods. The remaining lesions were followed with a mean of 31 months. The mean size of solid lesions detected by HHUS and ABUS was 7.67 mm (range 2.1-41 mm) and 7.74 mm (range 2-42 mm) respectively. The agreement for detection of cystic lesions between two methods for each breast was good (kappa: 0.61-0.62 p < 0.001). The agreement of two methods for solid mass lesions for each breast was moderate (k = 0.57-0.60 p < 0.001). There was good agreement between the two methods for detecting suspicious lesions (kappa = 0.66 p < 0.001). Conclusion: The level of agreement of ABUS and HHUS for dichotomic assignment of BIRADS categories was good. Although ABUS detected fewer lesions compared to HHUS, both methods detected all malignant lesions. ABUS is a reliable method for the detection of malignancy in dense breasts.