The present explorative study was initiated to evaluate the clinical value of 18F-FES PET/CT in monitoring the change of estrogen receptor (ER) expression and potential predictive value in metastatic breast cancer patients. Twenty-two pathology-confirmed breast cancer patients were prospectively enrolled and randomly divided into two groups (T: docetaxel, n = 14 and TF: docetaxel + fulvestrant, n = 8). The percentage of patients without disease progression after 12 months (PFS > 12 months) was 62.5% in group TF compared with 21.4% in group T (P = 0.08). According to 18F-FES PET/CT scans, the SUVmax (maximum standard uptake value) of all the metastatic lesions decreased in group TF after 2 cycles of treatment (6 weeks ± 3 days). However, 6 of 9 patients in group T had at least one lesion with higher post-treatment SUVmax. There was a significant difference in the reduction of ER expression between these two groups (P = 0.028). In group TF, the patients with PFS > 12 months had significantly greater SUVmax changes of 18F-FES than those with PFS < 12 months (PFS > 12 months: 91.0 ± 12.0% versus PFS < 12 months: 20.7 ± 16.2%; t = -4.64, P = 0.01). Our preliminary study showed that 18F-FES PET/CT, as a noninvasive method to monitor ER expression, could be utilized to predict prognosis based on changes in SUVmax.