Abstract: This paper describes a nonrigid registration method of multimodal medical images based on free form deformation, applied in image-guided noninvasive surgery. By the method, it registers pre-operative MRI or CT images with intra-operative ultrasound images based on the vessels visible in both of the modalities. When the images are aligned, the centerline points of the vessels in one image will align with the intensity ridge points in the other image. Rigid transformation is adopted in global registration while local deformation is described by a free form deformation based on a function controlled B-spline. The method applies an optimization strategy combining the genetic algorithm with the conjugated gradient algorithm to minimize the objective function. Two experiments were designed on phantom data and clinical data to evaluate the method, and the results indicate that the average standard deviation of the final transformation parameters is sub-voxel, sub-millimeter, and within 0.010 radians. The results show that the method has good registration accuracy and convergence rate. And it can be applied efficiently in the image-guided noninvasive surgery system.