Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A 4 (LXA 4 ) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA 4 inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1α level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA 4 could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA 4 suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis. Mol Cancer Ther; 9(8); 2164-74. ©2010 AACR.