We present a case of 64-year-old man with primary central nervous system lymphoma that mimicked encephalitis on enhanced MRI and F-FDG PET/CT imaging. The initial and follow-up MRI showed gradually spread high-intensity patches with nonenhancement in cortices and subcortices, while the F-FDG imaging observed mild and inhomogeneous uptake in the corresponding cerebral area particularly in the splenium of corpus callosum. This case indicates that atypical primary central nervous system lymphoma should be noted in differential diagnosis of cerebral disseminated lesions with nonenhancement in MRI or with obscure uptake of F-FDG in PET imaging (especially involving the midline of the brain).