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Abstract: Background: The aim of this study was to evaluate the clinical and economic consequences of the introduction of contrast-enhanced ultrasonography (CEUS) into the diagnostic clinical algorithm for the characterization of incidental focal liver lesions (FLLs). Methods: This prospective study enrolled 485 subjects at three hospitals in Italy. Two diagnostic algorithms were utilized: (1) a classic patient work-up, which included baseline US followed by a CT or MR examination, and (2) a new patient management scheme in which, following the baseline US, a CEUS examination was performed. For each pathway, both direct and indirect health costs for the National Health System (NHS) at two of the three hospitals involved in the study were calculated. Clinical outcome was measured in terms of number of cases correctly diagnosed, using contrast-enhanced CT/contrast-enhanced MR as the reference standard. Results: CEUS correctly differentiated (benign vs. malignant) 559 of 575 lesions (97.2%), with a sensitivity of 98.1% and a specificity of 95.7%. Histological characterization was correct in 502 of 575 lesions (87%) with a sensitivity of 90.5% and a specificity of 85.4%. In terms of cost, the conventional diagnostic algorithm incurred for the NHS a total cost of €134.576,60 vs. €55.674,30 with CEUS, for a saving of €78.902 (€162 per patient). For the hospitals, the total cost was €147.045 without CEUS vs €61.979 with CEUS, for a saving of €85.065,96 or €175,39 per patient. Conclusion: The routine use of CEUS for the characterization of FLLs provides significant cost savings, both for the NHS and for the hospital.