The role of angiogenesis in tumor progression has been recognized as one of the hallmarks of cancer, but the mechanism of its action remains unclear. Inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) are proposed to play causal roles in the development of various disorders, including malignancies. Previously, we identified the complex of CRP and SAA (CRP-SAA) with diagnostic and prognostic value better than either one of them in the serum of lung cancer patients. In this study, we further explored the stimulation function of CRP-SAA on angiogenesis and inflammation. To explore possible mechanisms, microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and multi-bioinformatics analysis revealed that THP-1 and human umbilical vein endothelial cells (HUVECs) responded to SAA stimulation with upregulation of two pro-angiogenic cytokines in common, i.e., C-X-C motif ligand 6 (CXCL6) and CXCL8, which were validated by subsequent experiments in vitro. CRP had weak effects as a single stimulus, but it can efficiently potentiate the SAA induction of cytokines, which was stronger than the sum of the both (P < 0.001). The synergistical effect of the combination of CRP and SAA enhanced HUVECs transwell and constricted morphology by upregulating the pro-angiogenic genes. These results indicated that the binding of CRP and SAA acted synergistically in pro-angiogenesis by increasing inflammation and inducing vascular network. © Copyright © 2020 Liu, Chen, Wang, Lei, Chen, Liang, Cheng, Shi, Wang, Lin, Wang, Lin, Lin and Liu.