Background: No validated prognostic biomarker is currently available for mCRC. This trial assessed cfDNA and MTV before treatment with regorafenib as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS) in mCRC. Methods: After signed informed consent, mCRC patients were enrolled in a prospective non-randomized trial aiming to define unlikelihood to benefit from regorafenib (EudraCT number: 2012-005655-16) and assessed for cfDNA and FDG PET/CT MTV at baseline. cfDNA was extracted from 3mL of plasma and quantified using the Qubit 2.0 fluorometer. All target lesions were delineated on FDG PET/CT using a PERCIST-based threshold and their volumes were summed to obtain total MTV. MTV and cfDNA optimal cutoffs for OS and PFS prediction were determined by the Contal and O’Quigley’s method. MTV, cfDNA, age, gender, Body Mass Index (low, normal, high, obese), ECOG PS, number of chemotherapy lines (NCL), previous use of bevacizumab and presence of a KRAS mutation were included in a multivariate analysis. Results: MTV and cfDNA of 132 evaluable/141 eligible patients were well correlated (Spearman’s correlation coefficient = 0.70; p < 0.001) and risk groups for both PFS and OS were identified on the basis of cfDNA (cfDNA < 1 µg/mL; cfDNA≥1 µg/mL) and MTV (MTV < 100 cm³; 100-300 cm³; > 300 cm³). The multivariate analysis retained cfDNA, MTV, NCL, and obesity as independent parameters for PFS prediction, and cfDNA, MTV, NCL, BMI, and previous use of bevacizumab as independent parameters for OS prediction. Prognostic scores for PFS and OS were developed based on regression coefficients from the final Cox proportional hazards models. Prognostic scores for PFS (1.8 vs 5.3 months, HR: 3.15 for score ≥-3 vs < -3, (95% CI, 2.08-4.76); p < 0.001) and for OS (4.2 vs 13.9 months, HR: 4.59 for score ≥-6 vs < -6: (95% CI, 2.92-7.21); p < 0.001) both identified patients with much contrasted outcomes. Conclusions: Baseline cfDNA and MTV along with BMI parameters predict outcome in patients with mCRC before regorafenib onset. These parameters not related to treatment should be considered, if validated in further studies, as stratification factors in future clinical trials. Clinical trial information: 2012-005655-16.