AIM: To investigate the effect of platelet (PLT) on angiogenesis in hepatocellular carcinoma and the intervention effect of Cinobufagin (CBG). METHODS: Firstly, we screened the suitable co-incubation ratio of PLT and hepatocellular carcinoma cells, prepared conditioned medium, and determined the half inhibitory concentration of Cinobufagin; then, we set up a control group (human umbilical vein endothelial cells (EC)+conventional medium), a crosstalk group (EC+CM_HP (strip culture prepared by crosstalk of HUH7 and PLT)), and an intervention group (EC+CM_HP+CBG). The migration, tube-formation and sprouting capacity of EC and the level of vascular endothelial growth factor (VEGF) in co-cultured supernatant were evaluated by scratch assay, tube-formation assay, budding assay and ELISA assay. Western blot was used to detect the expression of VEGFR2 and p-VEGFR2, and reverse verification was performed with inhibitors. A subcutaneous transplantation tumour model of hepatocellular carcinoma in nude mice was established, with Model group, Model+CBG group and Model+Apa group. The collagen expression of the transplantation tumour was observed by Masson staining, and the expression levels of vascular endothelial markers CD31 and CD34 were detected by immunofluorescence. RESULTS: When PLT : HUH7=200, the activity of HUH7 was the strongest, and the crosstalk between HUH7 and PLT significantly promoted the proliferation of EC (P<0.01). Compared with Control group, the migration, tube-formation and budding ability of Crosstalk group were enhanced, and those of Intervention group were lower than those of Crosstalk group (P<0.01). The expression level of VEGF in the supernatant of Crosstalk group was higher than that of Control group, while that of Intervention group was lower than that of Crosstalk group (P<0.01). The expression level of p-VEGFR2 protein in Crosstalk group was significantly higher than that of Control group, but the expression level of Intervention group was lower than that of Crosstalk group (P<0.01). Large collagen fibre deposition was seen in the Model group, and CBG intervention significantly reduced collagen fibre deposition in the transplanted tumour tissues. CD31 and CD34 expression was present in the hepatocellular carcinoma transplanted tumour tissues in the Model group, and CBG intervention significantly reduced the expression of CD31 and CD34 in the liver cancer transplanted tumour tissues (P<0.01). CONCLUSION: PLT enhances angiogenesis in hepatocellular carcinoma, and CBG may inhibit its tube-forming ability via the VEGF/VEGFR2 pathway.