A study was conducted to evaluate the feasibility of simultaneous dual radionuclide brain imaging with I-123 and Tc-99m using photopeak image subtraction techniques or offset photopeak image acquisition. The contribution of the photons from one radionuclide to a second radionuclide's photopeak energy window (crosstalk) was evaluated for SPECT and planar imaging of a brain phantom containing I-123 and Tc-99m for a range of activity levels and distribution properties approximating those in rCBF images of the adult human brain. Crosstalk was evaluated for 10% symmetrical energy windows centered on the I-123 and Tc-99m photopeaks and for 10% energy windows asymmetrically placed to the left and right of the center of the respective photopeaks. Major observations include: (1) in the centered photopeak windows, Tc-99m crosstalk in the I-123 window is 8.9% of the Tc-99m seen in the Tc-99m window and ranges from 37.5% to 75.0% of the I-123 in the I-123 window. I-123 crosstalk is 37.8% of the I-123 seen in the I-123 window and ranges from 4.4% to 8.9% of the Tc-99m seen in the Tc-99m window; (2) the spatial distribution of a radionuclide's crosstalk photons differs from that observed in the radionuclide's photopeak window; (3) a Tc-99m photopeak window offset to the left does not decrease I-123 crosstalk, and the percentage of Tc-99m scattered photons is significantly increased in the window. Offsetting the I-123 window to the right decreases Tc-99m crosstalk to 9.0% to 17.9% of the I-123 counts, but decreases I-123 sensitivity by 39.9%; and (4) offsetting both photopeak windows to the right decreases the Tc-99m scattered photons in the Tc-99m window, but increases I-123 crosstalk to 17.0% to 33.8% of the Tc-99m counts. The findings show that,image quality, spatial resolution, and quantitative accuracy are degraded to unacceptable levels with the combinations of energy windows tested for dual radionuclide imaging of Tc-99m and I-123. This indicates that dual radionuclide imaging must be thoroughly tested and validated before use in clinical studies.