Purpose: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor–positive (ERþ) breast cancer. Patients and Methods: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ERþ/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n ¼ 24) or fulvestrant-naïve cohort (n ¼ 11). Patients with ER-negative (ER)/HER2mut MBC received neratinib monotherapy in an exploratory ER cohort (n ¼ 5). Results: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%–62%), 30% (7%–65%), and 25% (1%–81%) in the fulvestrant-treated, fulvestrant-naïve, and ER cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. Conclusions: Neratinib and fulvestrant are active for ERþ/ HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.