Background <p>¹⁸F-Fluorodeoxyglucose (FDG) and ¹⁸F-Fluorestradiol (FES) have been FDA approved for measuring tumor glycolytic activity and estrogen receptor (ER) uptake, respectively, in clinical positron emission tomography (PET) imaging for patients with hormone-receptor (HR) positive metastatic breast cancer (MBC), but little is known about its utility in patients with breast tumors that overexpress human epidermal growth factor 2 (HER2). We hypothesize that comparing patterns of FDG and FES uptake in patients with HER2-positive versus HER2-negative MBC can guide further biologic and clinical studies into the HR/HER2-positive phenotype.</p> Methods <p>We conducted a retrospective study examining uptake in matched lesions for FES and FDG-PET scans, assessing these parameters in 213 patients with ER-positive/HER2-positive (<i>n</i> = 33) versus ER-positive/HER2-negative MBC (<i>n</i> = 180). We employed log-rank and t-tests to assess the association of HER2 status with outcome variables and the hypotheses that patients expressing HER2-positive disease lived longer than patient with HER2-negative disease.</p> Results <p>No difference in FES or FDG avidity was observed between patients with HER2-negative or HER2-positive tumor status. Limited data also suggests that patients with HER2-positive disease had better overall survival (<i>p</i> = 0.024), than those with HER2-negative disease, but not time-to-progression between the same patient cohorts.</p> Conclusion <p>This retrospective analysis suggests that there is a possible role for future trials using FES-PET in helping to select patients with ER+/HER2-positive primary tumors who retain ER expression at all sites of disease and may benefit from endocrine therapy.</p>