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An opportunistic spatio-frequency access (OSFA) strategy for cognitive radio (CR) multi-input multi-output (MIMO) system is proposed. When spectrum holes exist, cognitive service is implemented employing overlay approach. While there is no idle spectrum available, primary transmission mode information (PTMI) and inter-system interference channel information are utilized. And cognitive service is implemented using spectrum underlay. The method exploits both spatial correlation and eigenmode transmission gain in evaluation the quality of spatial resource. Consequently, selection diversity of both authorized channel and cognitive eigenmode is achieved. Moreover, PTMI based signal processing reduces the power loss of cognitive signal as well as antenna requirements for cognitive system. Simulation results show that the proposed strategy could achieve significant improvement of cognitive throughput on the premise that no interference is imposed on the primary.