Background: This study aimed to develop and validate a prognostic score integrating baseline metabolically active tumor volume (MATV) and clinical factors in metastatic colorectal cancer (mCRC) patients. Methods: The development cohort included chemorefractory mCRC patients enrolled in two prospective multicenter non-randomized trials evaluating sorafenib/regorafenib as last line therapy. The validation cohort included mCRC patients from another center, treated with chemotherapy and bevacizumab as first line. Baseline MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline ¹⁸F-FDG PET/CT. MATV optimal cutoff for OS prediction was determined from the development cohort with Contal and O’Quigley’s method. MATV, age, gender, BMI, ECOG PS, years since diagnosis, and KRAS status were included in a multivariate analysis. A prognostic score to predict OS was developed from the development cohort using Cox proportional hazards model. Results: MATV and clinical factors were evaluable respectively in 155 and 122 patients of the development and validation cohorts. In univariate analysis, MATV with cutoff set at 100 cm³ identified two risk groups with different median OS (mOS) in both the development (4.5 vs 10.9 months, HR: 2.64; p < 0.001) and validation cohorts (20.9 vs 42.9 months, HR: 2.39; p < 0.001). A multivariate analysis identified four independent negative predictors of OS (high MATV, short time since diagnosis, poor PS, BMI < 25). Combining these factors in a prognostic score for OS (best cutoff:-2) allowed to identify two risk groups with different mOS in the development (4.4 vs 13.4 months, HR: 3.67; p < 0.001) and validation cohorts (25 vs 63.8 months, HR: 2.5; p = 0.001). Conclusions: In mCRC patients, the high prognostic value of baseline MATV found in the development cohort was confirmed by external validation, independently of patients’ treatment. In both the development and validation cohorts the prognostic score for OS allowed to identify two risk groups of mCRC patients with significantly different mOS. MATV and our prognostic score for OS should provide a firm basis for risk stratification, in clinical practice and research trials.