Aim To assess the role of breast ultrasonography as a complement to negative mammography in radiologically dense breasts. Material and methods Out of a total series of 49,044 consecutive mammograms reported as negative in asymptomatic women, 25,665 (52.3%) were coded as dense (BI-RADS D3–4) and ultrasonography was recommended. Due to organizational problems, ultrasonography was performed immediately or within 1 month only in 5,227 cases, representing the study series. Results Two cancers were detected at immediate ultrasonography (0.03%). The cancer detection rate in women aged 40–49 and 50–69 years was 0.002% and 0.07%, respectively. The benign biopsy rate was 0.5% for core biopsies and 0.02% for surgical biopsies. The cost per ultrasonography-assessed woman was € 56.05, whereas the cost per additional mammographically occult but ultrasonography-detected cancer was € 146,496.53. The mammograms of the 2 cancer cases underwent blind review by an expert reader and were confirmed as negative. Discussion Our findings show a low cancer detection rate, substantially lower compared to other clinical studies of ultrasonography in dense breasts, though in accordance with preliminary evidence from an Italian randomized clinical trial within a population-based screening program. The policy of adding ultrasonography to negative mammography in dense breasts seems to have very limited cost-effectiveness, and should not be adopted in routine practice before results of ongoing clinical trials are available.