Multiple isotope simultaneous acquisition SPECT imaging can provide spatially and temporally registered images with just one image acquisition. We have previously demonstrated that, with model-based crosstalk compensation, simultaneously acquired 99mTc/201Tl dual-isotope cardiac imaging can provide images with quality and quantitative accuracy that is comparable with that from separate acquisition. Given the capability of modern SPECT systems to acquire projections in multiple energy windows, it is potentially possible to simultaneously assess rest and stress perfusion status with 201Tl and a 99mTc labeled agent, and innervation status with 123I-MIBG. However, because these three isotopes have very close emission energies and energy windows, crosstalk contamination can severely degrade the quality of simultaneously acquired images. In this work we developed a model-based method for estimating and compensating for the crosstalk and downscatter contamination in simultaneously acquired triple-isotope images. The crosstalk model includes the effects of the photon interactions inside the object and collimator-detector system. This crosstalk model was incorporated into the forward projection step of an iterative reconstruction algorithm to provide crosstalk compensation. We evaluated the proposed model-based method using Monte Carlo simulated simultaneous triple-isotope projection data. Results showed that there was very good agreement between the model-based estimates and the MC simulated projection data in each of the isotopes' energy windows. After compensation, the crosstalk in the simultaneously acquired images was effectively removed. In conclusion, we showed that it is possible to simultaneously acquire the cardiac SPECT imaging with 99mTc/ 201Tl/123I labeled multiple tracers. Using the proposed model-based crosstalk compensation method, the qualities of the simultaneously acquired triple-isotope images were comparable with the single acquisitions.