Fusion of anatomic information in computed tomography (CT) and functional information in 18F-FDG positron emission tomography (PET) is crucial for accurate differentiation of tumor from benign masses, designing radiotherapy treatment plan and staging of cancer. Although current PET and CT images can be acquired from combined 18F-FDG PET/CT scanner, the two acquisitions are scanned separately and take a long time, which may induce potential positional errors in global and local caused by respiratory motion or organ peristalsis. So registration (alignment) of whole-body PET and CT images is a prerequisite for their meaningful fusion. The purpose of this study was to assess the performance of two multimodal registration algorithms for aligning PET and CT images. The proposed gradient of mutual information (GMI)-based demons algorithm, which incorporated the GMI between two images as an external force to facilitate the alignment, was compared with the point-wise mutual information (PMI) diffeomorphic-based demons algorithm whose external force was modified by replacing the image intensity difference in diffeomorphic demons algorithm with the PMI to make it appropriate for multimodal image registration. Eight patients with esophageal cancer(s) were enrolled in this IRB-approved study. Whole-body PET and CT images were acquired from a combined 18F-FDG PET/CT scanner for each patient. The modified Hausdorff distance (d(MH)) was used to evaluate the registration accuracy of the two algorithms. Of all patients, the mean values and standard deviations (SDs) of d(MH) were 6.65 (± 1.90) voxels and 6.01 (± 1.90) after the GMI-based demons and the PMI diffeomorphic-based demons registration algorithms respectively. Preliminary results on oncological patients showed that the respiratory motion and organ peristalsis in PET/CT esophageal images could not be neglected, although a combined 18F-FDG PET/CT scanner was used for image acquisition. The PMI diffeomorphic-based demons algorithm was more accurate than the GMI-based demons algorithm in registering PET/CT esophageal images.