Real time 3D medical image registration method is key technology of medical image processing, especially in surgical operation navigation. However, current 3D medical image registration methods are time-consuming, which can’t meet the real time requirement of clinical application. To solve this problem, this paper presented a high performance computational method based on CUDA ( Compute Unified Device Architecture), which took full advantage of GPU parallel computing under CUDA architecture combined with image multiple scale and maximum mutual information to make fast registration of three dimensional medical image. Experiments showed that this algorithm can greatly accelerate the computational speed of registration of three dimensional medical image, and meet the real time requirement of clinical application.