Purpose <p>To assess whether arterial computed tomography portography guidance improves early local tumor control after percutaneous thermal ablation of small colorectal cancer liver metastases compared with standard-of-care imaging guidance, hypothesizing a ≥ 20% increase in complete ablation at 3&#xa0;months confirmed by MRI and PET-CT.</p> Materials and Methods <p>This prospective, single-blind, two-center trial will randomize 88 adults (1:1) with up to three colorectal liver metastases ≤ 3&#xa0;cm, including at least one not visible with ultrasound, to undergo ablation under either standard imaging guidance (intravenous contrast-enhanced CT, image fusion, or CT hepatic arteriography) or arterial portography after selective mesenteric or splenic catheterization in a hybrid angio-CT suite. Operators may use radiofrequency or microwave devices. The primary endpoint is complete ablation at 3&#xa0;months on MRI and PET-CT. Secondary endpoints include lesion-level success, 12-month recurrence, safety, and a translational biobank. The sample size provides 80% power to detect a 20% absolute improvement (two-sided <i>α</i> = 0.05).</p> Results <p>Not applicable; protocol manuscript.</p> Expected Gain of Knowledge <p>The MARGIN trial will test whether arterial CT portography can improve complete ablation rates versus standard imaging in colorectal liver metastases. Beyond technical outcomes, it aims to refine image guidance strategies, optimize margin control, and generate high-level evidence for interventional oncology. The translational biobank will further link imaging findings to tumor biology and immune activation.</p> Conclusion <p>This trial will test if arterial CT portography can improve early completeness of thermal ablation for colorectal liver metastases versus standard imaging.</p> Trial Registration <p>ClinicalTrials.gov&#xa0;NCT05665322 (registered December 14, 2022).</p> Level of Evidence <p>Level 1b (randomized controlled trial).</p> Graphical Abstract <p></p>