In SPECT, simultaneous (99m)Tc/(123)I acquisitions allow comparison of the distribution of two radiotracers in the same physiological state, without any image misregistration, but images can be severely distorted due to cross-talk between the two isotopes. We propose a generalized spectral factor analysis (GSFA) method for solving the cross-talk issue in simultaneous (99m)Tc/(123)I SPECT. In GSFA, the energy spectrum of the photons in any pixel is expressed as a linear combination of five common spectra: (99m)Tc and (123)I photopeaks and three scatter spectra. These basis spectra are estimated from a factor analysis of all spectra using physical priors (e.g. Klein-Nishina distributions). GSFA was evaluated on (99m)Tc/(123)I Monte Carlo simulated data and compared to images obtained using recommended spectral windows (WIN) and to the gold standard (GS) images (scatter-free, cross-talk-free and noise-free). Using GSFA, activity concentration differed by less than 9% compared to GS values against differences from -23% to 110% with WIN in the (123)I and (99m)Tc images respectively. Using GSFA, simultaneous (99m)Tc/(123)I imaging can yield images of similar quantitative accuracy as when using sequential and scatter-free (99m)Tc/(123)I imaging in brain SPECT.