OBJECTIVE Our purpose was to describe a novel, rapid stress thallium-201 (Tl-201)/rest technetium-99m (Tc-99m) agent myocardial perfusion imaging (MPI) protocol (Tl/Tc) with a high-speed MPI scanner and to compare this protocol with a standard rest/stress Tc-99m agent protocol (Tc/Tc) with respect to image quality and radiation dosimetry. BACKGROUND Recent advances in gamma camera technology have provided opportunity for improved SPECT MPI protocols. A rapid Tl/Tc protocol that could improve image information while maintaining a low radiation burden for the patient would be desirable. METHODS We compared high-speed SPECT MPI studies in 374 consecutive patients undergoing exercise or pharmacologic Tl/Tc protocol to those of 262 patients undergoing rest/stress Tc/Tc protocol. RESULTS Tl/Tc imaging was accomplished in <20 min. Overall image quality was good to excellent in 96% and 98% of patients with the Tl/Tc and the Tc/Tc protocols, respectively (p = ns). Beginning rest imaging within 2 min after rest injection with the Tl/Tc protocol did not result in reduced confidence in image interpretation. Early rest Tc images of the Tl/Tc protocol showed less extracardiac activity than was observed on standard rest imaging used in the Tc/Tc protocol (84% vs. 61%), respectively (p < 0.01). The normalcy rate was high in both groups (100% vs. 92%). Radiation burden was similar between the Tl/Tc and Tc/Tc protocols. CONCLUSIONS A rapid stress Tl-201/rest Tc-99m protocol for use with high-speed SPECT MPI has image quality and radiation dosimetry similar to those observed with a conventional rest/stress Tc-99m protocol. The Tl/Tc protocol offers promise as an efficient and relatively low radiation dose method, in which the superior qualities of Tl-201 for stress imaging and of the Tc-99m agents for rest imaging can be preserved. The findings also suggest that with rapid imaging rest MPI immediately after Tc-99m agent injection may be superior to standard delayed image initiation.