Co-registration of brain SPECT and MR images has been used extensively in clinical applications. The complementary features of two major co-registration methods--surface- and mutual-information-based (MI-based)--motivated us to study a hybrid-based scheme that uses the surface-based method to achieve a quick alignment, followed by the MI-based method for fine tuning. Computer simulations were conducted to evaluate the accuracy and robustness of surface-, MI-, and hybrid-based registration methods by designing different levels of noise and mismatch in the registration experiments. Results demonstrated that the hybrid surface-MI-based scheme outperforms both the surface- and MI-based methods in providing superior accuracy and success rates. Specifically, the translational and rotational errors were no more than 1 mm and 2°, respectively, with consistent success rates over 98%. Besides, the hybrid-based method saved 12-53% of the computation efforts, compared with using the MI-based method alone. We recommend the use of hybrid-based method when the orientational differences between the floating and reference images exceed 10°.