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Herein, advantaging the multitargeting antitumor effects and normal organ-protecting roles of Chinese herbal medicine, the aim of this study was to investigate the enhanced synergistic efficacy of fulvestrant plus Tan IIA combination therapy in ER-positive breast cancers and to monitor the early response by longitudinal <jats:sup>18<\/jats:sup>F-FES PET\/CT imaging. The experimental results showed FUL\u2009+\u2009Tan IIA combination therapy significantly inhibited tumor growth of ER-positive ZR-75-1 tumor xenografts and exhibited distinct antitumor effects at an earlier time point after treatment than did the monotherapy of FUL or Tan IIA. Moreover, <jats:sup>18<\/jats:sup>F-FES PET\/CT imaging competently monitored the early response of FUL\u2009+\u2009Tan IIA combination therapy. The quantitative <jats:sup>18<\/jats:sup>F-FES %ID\/g<jats:sub>max<\/jats:sub> in vivo was further confirmed by and correlated well with ER<jats:italic>\u03b1<\/jats:italic> expression ex vivo. 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