In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab-based chemotherapy in two independent prospective clinical trials (development set: n5126, validation set: n551, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p50.0066) and log-CD138 high level (p50.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS5 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C-index50.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values.