Abstract Purpose This study evaluated the ability of 18 F-Fluorodeoxyglucose (FDG) and 18 F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. Methods In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET ( n  = 22) or FLT-PET ( n  = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. Results FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range −45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range −77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery mean 8% (range < 1 to 41%). Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. Conclusions A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.