Background: The recently FDA approved ¹⁸F-Fluoroestradiol (FES) is a PET imaging tracer for characterizing disease in patients with ER+ breast cancer. As FES PET enters clinical practice it will be important to establish its utility in the full population of hormone-receptor positive patients, including those with HER2+ tumors. Historically the consensus around ER+/HER+ disease has been that these tumors are primarily driven by HER2, with therapies focused on targeting this pathway. Emerging research suggests that ER+ and HER2+ tumors represent a distinct phenotype, with bidirectional crosstalk between ER and HER2 pathways contributing to resistance to therapies targeting these critical pathways. Methods: Our cross-sectional database of patients with one or more FES scans stretches back to 1996. We selected all patients with HER2+ advanced breast cancer to determine whether ER is functional in the ER+/HER2+ subset. We examined paired FDG and FES scans and recorded SUVmax in matched lesions between the FDG and FES scans. We also looked at a subset of patients who underwent scans at more than one time-points and examined the clinical characteristics of these cases over time. Results: 36 patients with metastatic ER+, HER2+ breast cancer underwent concurrent FDG and FES PET scans between 1996 and 2013. 34 subjects (94%) were female; 32 (89%) were Caucasian, and 4 (11%) were Asian. Eight patients underwent serial scans. A total of 200 metastatic sites were recorded with the majority (67%) being bony lesions. No difference in quantitative FES avidity was observed between soft tissue and osseous sites. Six patients (16%) had negative FES scans despite displaying FDG avid lesions; three patients had at least one negative FES scan on serial scans, and two demonstrated FES-avid lesions with no FDG activity. Average FES SUVmax for positive scans was 3.5, with a range of 0.8 to 10.7. Among eight patients with multiple scans, half had 2 scans, three had 3 scans, and one had 4 scans. In 7/8 patients (88%) FES avidity increased over time even as FDG decreased or stayed stable with treatment; in one, both FES and FDG decreased on follow up scan. Conclusions: In a cohort of ER+, HER2+ patients undergoing FDG and FES PET scans, robust concordance between FDG and FES uptake was observed. FES avidity increased in patients with multiple scans, suggesting that the ER pathway remained active during treatment. The strong FES positivity in many HER2+ patients in this cohort suggests that FES PET could be used to guide patient selection for trials examining deescalated regimens employing a non-chemotherapy partner for HER2-directed therapy or emphasizing more ER-directed therapies such as CDK4/6 inhibitors, which are not currently approved in this population. With the ongoing development of HER2- PET imaging, combination scans could carry the potential for discrimination between sites, possibly serving as a tool to guide biopsy.