HER2 overexpression in breast cancer confers increased tumor aggressiveness. Although anti-HER2 therapies have improved patient outcome, resistance ultimately occurs. PARP inhibitors target homologous recombination (HR)-de fi cient tumors, such as the BRCA-associated breast and ovarian cancers. In this study, we show that HER2+ breast cancers are susceptible to PARP inhibition independent of an HR deficiency. HER2 overexpression in HER2 negative breast cancer cells was sufficient to render cells susceptible to the PARP inhibitors ABT-888 and AZD-2281 both in vitro and in vivo, which was abrogated by HER2 reduction. In addition, ABT-888 significantly inhibited NF-κB (p65/RelA) transcriptional activity in HER2+ but not HER2 negative breast cancer cells. This corresponded with a reduction in phosphorylated p65 and total IKKα levels, with a concomitant increase in IκBα. Overexpression of p65 abrogated cellular sensitivity to ABT-888, whereas IκBα overexpression reduced cell viability to a similar extent as ABT-888. Therefore, susceptibility of HER2+ breast cancer cells to PARP inhibition may be because of inhibition of NF-κB signaling driven by HER2. Our fi ndings indicate that PARP inhibitors may be a novel therapeutic strategy for sporadic HER2+ breast cancer patients. ©2012 AACR.