Breast cancer, especially estrogen receptor (ER)‐negative breast cancer, remains hard to treat despite major advances in surgery and adjuvant therapies. The deletion of ER has been consistently associated with tumor progression, recurrence, metastasis and poor prognosis. Among other differences in biological features, ER‐negative breast cancers express high levels of interleukin‐8 (IL‐8), whereas their ER‐positive counterparts do not. IL‐8 is a multi‐functional cytokine with many important biological functions in tumor formation and development. We aimed to study the role(s) of IL‐8 in ER‐negative breast cancer progression by using RNA interference to specifically knockdown IL‐8 expression in ER‐negative breast cancer cell lines MDA‐MB‐231 and MDA‐MB‐468. In vitro, suppression of IL‐8 led to significant reductions in cell invasion (p < 0.001), but had no effects on cell proliferation or cell cycle. In vivo, suppression of IL‐8 significantly reduced the microvessel density (p < 0.05), and markedly reduced neutrophil infiltration into the tumors (p < 0.05). In contrast to in vitro observations, suppression of IL‐8 promoted tumor growth in nude mice (p < 0.05). Our results imply that the complex roles of IL‐8 in the regulation of ER‐negative breast cancer progression may in part be related to its potent chemotactic effects on neutrophils, which in turn mediates many of the biological functions of IL‐8. © 2007 Wiley‐Liss, Inc.