Soluble CD46 (sCD46) has recently been shown to be an effective biomarker of steatotic liver disease (SLD), which is highly prevalent in the western world. Since SLD directly affects outcomes after major hepatectomies and liver transplantation, accurate appraisal of this condition is crucial before liver surgery. In the present study, we asked whether sCD46 measurement in patient plasma could augment the pre-surgical prediction of SLD performed by contrast-enhanced computed tomography. Our data show that combined performance of these tests reveals an area under the curve for the prediction of high-grade SLD of 0.956. After cross-validation, our clinical score leads to an accuracy of 95.12% to detect severe steatosis. Therefore, sCD46 is a promising biomarker for optimizing pre-surgical decision-making assessments, with the aim to identify patients that could benefit from alternative treatment options.