Objectives: To determine whether diffusion-weighted imaging (DWI) can help to distinguish early stage autoimmune (AI) and herpes simplex virus (HSV) encephalitides. Methods: This case-control study included patients from a multi-center cohort of AI encephalitides whose initial MRI including DWI was performed within ten days after symptoms onset. They were compared with patients with HSV encephalitis enrolled prospectively in a single-center from June, 2020 to December, 2020. The final diagnosis of AI encephalitis required a positive autoantibody assay, and that of HSV encephalitis required a positive HSV polymerase chain reaction based on cerebrospinal fluid. Brain MRI were evaluated for restricted diffusion, fluid-inversion recovery (FLAIR) abnormalities, lesion topography, hemorrhagic changes, and contrast enhancement. Results: Forty-nine patients were included of which, 19 (38.8%) had AI encephalitis. Twenty-seven patients (55.1%) were males and the median age was 46.0 years (interquartile range (IQR):[22.0; 65.0]). Brain MRI were performed after a median of 4 days (IQR:[2.0; 7.0]) of symptom onset and time between symptom onset and MRI was not significantly different (p = 0.60). Twenty-six patients had restricted diffusion lesions in the medial temporal lobe, including 25/30 in the HSV encephalitis group (p < 0.001). FLAIR abnormalities were observed in 36 patients, including 29/30 in the HSV encephalitis group (p < 0.001). Lesion topography, hemorrhagic changes, and contrast enhancement did not differ significantly between the two groups. Conclusion: Our results suggest that restricted diffusion lesions in the medial temporal lobe are a hallmark of HSV encephalitis and may help distinguish it from early-stage AI encephalitis.