Hamfjord J, Guren TK, Glimelius B, et al. - Given that identification of tumour‐specific circulating cell‐free DNA in plasma (ctDNA) fails in a significant number of cases based on the clinical context, researchers herein inquired about the clinicopathological factors related to identification of ctDNA in patients with RAS‐/BRAF‐mutated metastatic colorectal cancer (mCRC) before first‐line therapy. They also assessed the prognostic influence of ctDNA vs other biomarkers. Patients were selected from the NORDIC‐VII study (N = 253). Factors that were related to mutation detection in plasma were: increasing radiological size of target lesions by increments of 1 cm, intact primary tumour and more than one metastatic site. Metastatic involvement of the lung was identified to be related to non‐detection. Detection was modulated by pre‐analytical and analytical factors. A poor prognosis was suggested by high allele frequencies of ctDNA, independently of CEA and CA19‐9. Carefully considering clinicopathological features is recommended when assessing ctDNA results from mCRC cases, particularly when confronted with a plasma negative result. ctDNA may prove to represent a clinically beneficial marker in the assessment of mCRC management.