Objective <p>This study evaluated the prognostic value of synthetic tumor extracellular volume fraction (ECV) and its association with somatic gene alternations in patients with colorectal liver metastases (CRLM) receiving neoadjuvant chemotherapy.</p> Methods <p>This retrospective single-center study included patients undergoing curative hepatectomy after neoadjuvant chemotherapy for CRLM (2013–2020). Contrast-enhanced computed tomography (CT) studies obtained after neoadjuvant chemotherapy were used to calculate synthetic ECV and synthetic hematocrit by linear regression analysis. Patients were grouped according to synthetic ECV cutoff point based on the Youden index. Multivariate analyses were performed with Cox regression models to analyze the prognostic factors of overall survival (OS) and recurrence-free survival (RFS).</p> Results <p>A total of 209 patients (median age 56 years, 119 men) were enrolled. Synthetic ECV correlated well with conventional ECV (<i>r</i> = 0.996, <i>p</i> &lt; 0.0001) with minimal bias, according to the Bland–Altman analysis (bias = 0.007). The optimal synthetic ECV cutoff point was determined to be 21%, with 115 patients having high ECV and 94 low ECV. Multivariable analysis for predicting high ECV demonstrated significant associations with synchronous CRLM, anti-VEGF agent-containing regimen, and <i>RAS-BRAF</i> mutation (<i>p</i> = 0.022, &lt; 0.001, and = 0.003, respectively). OS and RFS were significantly higher in the high ECV group compared to the low ECV group (<i>p</i> = 0.019 and <i>p</i> = 0.015, respectively). High ECV was independently associated with improved OS (HR 0.55, 95% CI 0.34–0.91) and RFS (HR 0.71, 95% CI 0.52–0.97).</p> Conclusions <p>Synthetic ECV can help predict OS and RFS in patients undergoing curative-intent CRLM resection after neoadjuvant chemotherapy and could be a useful imaging biomarker to stratify risk.</p> Key Points <p><Emphasis Type="BoldItalic">Question</Emphasis><i> There is a need for a biomarker predictive of treatment response after neoadjuvant chemotherapy, prior to curative-intent colorectal liver metastases.</i></p> <p><Emphasis Type="BoldItalic">Findings</Emphasis><i> Synthetic extracellular volume fraction can help predict overall and recurrence-free survival and is associated with somatic gene alterations.</i></p> <p><Emphasis Type="BoldItalic">Clinical relevance</Emphasis><i> Prognostic markers of response to neoadjuvant chemotherapy in curative-intent colorectal liver metastases include extracellular volume fraction. Synthetic extracellular volume fraction obviates the need for hematocrit; a simplification that is expected to streamline routine clinical practice.</i></p> Graphical Abstract <p></p>