Both cyclooxygenase (COX)‐2 and human epidermal growth factor receptor (HER)‐2 promote breast cancer progression; however, the relationship between the two molecules remains unclear. We utilized human breast cancer tissues and cell lines to examine whether COX‐2 and HER‐2 played independent or interdependent roles in vascular endothelial growth factor (VEGF)‐C up‐regulation and lymphangiogenesis. A paired correlation of immunodetectable levels of COX‐2, VEGF‐C, and HER‐2 proteins and lymphovascular density (LVD; D2‐40‐immunolabeled) in 55 breast cancer specimens revealed a positive correlation between COX‐2 and HER‐2 irrespective of clinicopathological status. However COX‐2 alone positively correlated with LVD. In 10 independent specimens, mRNA levels showed a positive correlation between HER‐2 and COX‐2 or VEGF‐C but not LYVE‐1 (lymphovascular endothelial marker). These findings implicate COX‐2, but not HER‐2, in breast cancer–associated lymphangiogenesis. Manipulation of the COX‐2 or HER‐2 genes in breast cancer cell lines varying widely in COX‐2 and HER‐2 expression revealed a direct role of COX‐2 and an indirect COX‐2 dependent role of HER‐2 in VEGF‐C up‐regulation: (i) high VEGF‐C expression in high COX‐2/low HER‐2 expressing MDA‐MB‐231 cells was reduced by siRNA‐mediated down‐regulation of COX‐2, but not HER‐2; (ii) integration of HER‐2 in these cells simultaneously up‐regulated COX‐2 protein as well as VEGF‐C secretion; and (iii) low VEGF‐C secretion by high HER‐2/low COX‐2 expressing SK‐BR‐3 cells was stimulated by COX‐2 overexpression. These findings of the primary role of COX‐2 and the COX‐2‐dependent role of HER‐2, if any, in VEGF‐C up‐regulation and lymphangiogenesis suggest that COX‐2 inhibitors may abrogate lymphatic metastasis in breast cancer irrespective of HER‐2 status. (Cancer Sci 2010)