OBJECTIVES: Liver imaging techniques aim to correctly characterize focal lesions and influence choices of therapeutic strategies. The objective of this study was to compare diagnostic efficacy and direct medical costs of contrast-enhanced ultrasound (CEUS) to magnetic resonance imaging (MRI) or computed tomography (CT) in the characterization of focal liver lesions in the Netherlands. METHODS: This prospective study enrolled 170 patients at an academic hospital in the Netherlands. A decision model was designed to compare two diagnostic algorithms based on the results of the study: 1) a typical patient work-up, which included ultrasound (US), followed by an MRI or CT examination, and 2) a new patient work-up in which CEUS was performed after US. The perspective of the healthcare sector in the Netherlands was used. Clinical outcomes were `correctly characterizedx benign and malignant liver lesions and life-years (LY). Model inputs were taken from the hospital database, literature and publicly available sources. Time horizon was two years. One-way and probabilistic sensitivity analyses were performed to assess uncertainty in the results. RESULTS: CEUS was able to identify benign and malignant focal liver lesions with a sensitivity of 96.9% and specificity of 92.3%. For correct tumor subgroup characterization, sensitivity and specificity were 86.2% and 85.6% respectively. Base-case results revealed that the CEUS strategy had similar effectiveness compared to the MRI/CT strategy (incremental effects of 0.002 LYs) and resulted in cost-savings of €452. The cost-savings for diagnostic phase and treatment phase were €160 and €292 respectively. The results were sensitive to specificity, sensitivity and cost of the diagnostic tests. Robustness of the results was confirmed by probabilistic sensitivity analysis.  CONCLUSIONS: This study demonstrates that CEUS is a cost-saving alternative compared to the traditional diagnostic procedures and should be considered as one of the `first stepx options in the front-line characterization of focal liver lesions in the Netherlands.