Angiogenesis plays an important role in tumour growth and dissemination. We have recently shown that blood vessel density, determined by image analysis based on microRNA-126 (miRNA-126) in situ hybridization (ISH) in the primary tumours of metastatic colorectal cancers (mCRC), is predictive of chemotherapy response. Here, we evaluated whether more general approaches to determine vessel density in primary tumours are equally predictive of chemotherapy response.This methodological study was carried out using paraffin embedded tissues from primary tumours of 89 patients with mCRC, who had all been treated with first-line chemotherapy (XELOX). Tissue sections from the deepest invasive tumour front were processed for miRNA-126 ISH and CD34 immunohistochemistry (IHC). Estimates of microvessel density (MVD) were obtained for both miRNA-126 and CD34 by quantitative image analyses (MVDi), vascular area per image (μm²) analyses, and manually counting vessels in vascular hot spots (MVDh). Clinical responses were evaluated according to Response Evaluation Criteria In Solid Tumours (RECIST).The MVDi for miRNA-126 showed a significant correlation with treatment response (p=0.01), with a median value of 2,071 μm² (95% CI, 1,505-3,075 μm²) in the responder group compared to 1,337 μm² (95% CI, 1,038-1,499 μm²) in the non-responder group. This difference translated into a significant difference in progression free survival (p=0.01).The methodological assessment of MVD and the molecular vessel marker are both important for the prediction of the chemotherapy response in mCRC. Our findings indicate that MVDi for miRNA-126 represents a powerful estimate and may serve as a clinical biomarker superior to MVDh.