Purpose <p>Receptor discordance between primary and metastatic breast cancer is increasingly recognized and may influence treatment decisions in metastatic breast cancer (MBC) patients. ¹⁸F-fluoroestradiol (¹⁸F-FES) PET/CT enables non-invasive whole-body assessment of estrogen receptor (ER) expression and may provide additional information beyond tissue-based evaluation. This study aimed to investigate the clinical significance of ¹⁸F-FES-positive conversion in patients with MBC whose primary tumors were ER-negative, and to evaluate the potential role of ¹⁸F-FES PET/CT in treatment stratification.</p> Methods <p>This retrospective study screened 1330 patients with metastatic breast cancer who underwent ¹⁸F-FES PET/CT, identified 51 patients with ER-negative primary breast tumors, and finally included 40 evaluable patients in the analysis. ¹⁸F-FES positivity was defined by focal uptake visually distinguishable from local background together with a lesional SUVmax ≥ 1.8. Progression-free survival (PFS) was estimated using the Kaplan–Meier method and compared using the log-rank test.</p> Results <p>¹⁸F-FES-positive conversion occurred in 37.5% (15/40) of patients. Primary progesterone receptor (PR) positivity was more frequent in patients with ¹⁸F-FES-positive conversion than in those without conversion (60.0% vs. 24.0%; <i>P</i> = 0.042). After imaging, endocrine-based therapy predominated among patients with ¹⁸F-FES-positive conversion whereas chemotherapy was more common in ¹⁸F-FES-negative patients. Patients with ¹⁸F-FES-positive conversion showed significantly longer PFS than those remaining ¹⁸F-FES-negative (median PFS, 15.2 vs. 7.3 months; <i>P</i> = 0.005).</p> Conclusion <p>ER-positive conversion assessed by ¹⁸F-FES PET/CT can occur in clinically selected patients with metastatic breast cancer and ER-negative primary tumors. ¹⁸F-FES PET/CT may provide clinically meaningful information for treatment stratification in this patient population.</p>