Neoadjuvant chemotherapy (NACT) is the treatment of choice in patients (pts) with locally advanced (LABC) and inflammatory breast cancer (IBC). To evaluate the role of Tc-99m sestamibi imaging in the prediction of response to NACT and in the in vivo functional detection of intrinsic or acquired chemoresistance, 24 female pts with LABC (n=21) or IBC (n=3) were prospectively studied. Tc-99m scintimammography was performed 1-3 days before treatment (first) and 2-5 days after the completion (second) of NACT (epirubicin and cyclophosphamide for LABC and doxorubicin and vinorelbine for IBC). Three planar images (2 lateral prone and one anterior supine, 10 min/each) were obtained 10 min postinjection and a lateral prone image (10 min) of the affected breast (B) was obtained at 4 h. To calculate the tumor to normal B ratio (TBR), 2 identical irregular regions of interest (ROIs) were drawn around the tumor (T) and in adjacent ipsilateral normal B on both early (E) and delayed (D) prone lateral images. The TBR was obtained as the ratio of the mean counts per pixels in the 2 ROIs. Then Tc-99m sestamibi retention index (RI) in the T was determined by dividing the D-TBR by the E-TBR. Afterwards, NACT response was assessed pathologically or clinically in inoperable disease. Scintigraphic sensitivity for correct prediction of T presence after NACT was 81% (17/21), whereas specificity for correct prediction of T absence was 100% (3/3). In LABC, 3 patients had a pathological complete response: first RI was high (>0.56) in all 3, while no T uptake was visible on the second scintigraphy. Eighteen patients did not show a pathological complete response: in 5, both first and second RI were low (</=0.56); 9 had high first RI but low second; 4 had high first RI and no T detected on the second scan. In IBC, the only patient with a clinical complete response had both first and second RI high, whereas the 2 non-responsive pts had both first and second RI low. These results indicate that Tc-99m sestamibi scintimammography can predict LABC and IBC response to NACT. The scintigraphy protocol, including 2 studies before and after NACT, is useful for detecting intrinsic and acquired chemoresistant BC in vivo, which is important for planning therapy and predicting prognosis.