Background and aim <p>The positive detection rate of MRI in autoimmune encephalitis (AIE) patients is low, often failing to make a rapid and accurate localization diagnosis. Both ¹⁸F-DPA714 and ¹⁸F-FDG PET imaging techniques have shown their advantages in the diagnosis of AIE. Therefore, the aim of this study was to conduct a head-to-head comparison of the diagnostic value between ¹⁸F-DPA714 and ¹⁸F-FDG PET in patients with AIE.</p> Methods <p>This cross-sectional study included 23 antibody-positive and 2 possible antibody-negative AIE patients, along with 10 healthy controls. All patients underwent sequential ¹⁸F-DPA714 PET/MRI and ¹⁸F-FDG PET/CT examinations within one week. A follow-up of 6 to 12&#xa0;months after the baseline examinations was performed to assess the change of patients' clinical symptoms. Positive findings for ¹⁸F-DPA714 PET were defined as Z-score above 2.0 in the corresponding brain regions of healthy controls. Positive results for ¹⁸F-FDG PET were indicated by the Z-score above 2.0 or below -2.0 obtained after comparison with the normal population database.</p> Results <p>Both ¹⁸F-FDG PET and ¹⁸F-DPA714 PET showed higher positivity rates than MRI (81% vs 44%, <i>P</i> = 0.006 and 76% vs 44%, <i>P</i> = 0.008, respectively). A statistically significant association was found between the uptake intensity and extent of ¹⁸F-DPA714 but not ¹⁸F-FDG with the mRS scores and the CASE scores. Patients with epilepsy showed a significantly higher uptake in the whole-cortex of both ¹⁸F-DPA714 (<i>P</i> = 0.0014) and ¹⁸F-FDG (<i>P</i> = 0.0051) and in the temporal lobe of ¹⁸F-FDG (<i>P</i> = 0.0216) compared to those patients without. Higher ¹⁸F-DPA714 SUVR (<i>P</i> &lt; 0.001) and lower ¹⁸F-FDG SUVR (<i>P</i> &lt; 0.001) in the whole-cortex of patients with long-term cognitive impairment than those patients without were observed.</p> Conclusion <p>¹⁸F-DPA714 PET showed its better correlation with disease severity of AIE than ¹⁸F-FDG PET, serving as a supplementary tool to ¹⁸F-FDG PET and MRI.</p>