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Myocardial perfusion imaging (MPI) with single‐photon emission computed tomography (SPECT) is an important tool in the clinical management of heart disease. Simultaneous dual‐istope imaging offers a means to greatly reduce the time required for this test, but is limited by interference between the signals of the two isotopes. Newly developed dedicated cardiac SPECT cameras based on CZT detectors may reduce the interference between isotopes due to improved energy resolution. Our objective is to measure in clinical patients the magnitude of cross‐talk expected for simultaneous perfusion imaging with Tl‐201 and Tc‐99m‐tetrofosmin on a new CZT‐based multi‐pinhole dedicated cardiac SPECT camera. We retrospectively examined 25 matched pairs of Tl‐201 and Tc‐99m‐tetrofosmin patients. Reprocessing the listmode data, we determined the cross‐talk fraction for typical energy windows as well as for a Tc‐99m energy window that was reduced from 20% to 12%. Two protocols were considered: Tl‐rest/Tc‐stress and Tc‐rest / Tl‐stress. Cross‐talk into the Tl window was 74% and 36% respectively for the two protocols. Cross‐talk into the 10% Tc‐99m window was 2.4% and 11% respectively. The cross‐talk into the Tc‐99m window was reduced by 25% using a +/−6% window. Cross‐talk between Tc‐99m‐tetrofosmin and Tl‐201 has been assessed for the new dedicated CZT‐based cardiac SPECT cameras and the improved energy resolution of the CZT detectors decreases cross‐talk interference.