Background <p>This study aims to determine whether 4 weeks of adjunctive minocycline can improve cognitive and neurological symptoms in patients with autoimmune encephalitis (AE).</p> Methods <p>In this randomized, open-label, blinded-endpoint trial, participants were randomized (1:1) to receive first-line immunotherapy with or without minocycline (100&#xa0;mg twice daily for 4 weeks). Clinical outcomes included changes in the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), modified Rankin Scale (mRS), and Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The exploratory outcome was the change in Soluble Triggering Receptor Expressed on Myeloid cells 2 (sTREM2), a biomarker of microglial activation. Follow-up assessments were conducted at weeks 4, 12, 24, and 48.</p> Results <p>Sixty patients with AE were enrolled. For the primary outcome, the difference in mean change in MoCA scores between the groups was 1.05 (<i>P</i> = 0.46) from baseline to week 12. However, at week 4, the minocycline group demonstrated significantly improvements in MoCA (difference, 3.85; 95% CI, 1.04 to 6.66; <i>P</i> = 0.008) and MMSE (difference, 3.23; 95% CI, 0.20 to 6.26; <i>P</i> = 0.037) compared to the control group. CSF sTREM2 levels decreased in the minocycline group (difference, –93.3; 95% CI, –186.60 to –0.05; <i>P</i> = 0.050). No other secondary outcomes differed between groups. Adverse events were mild, and no allergic reactions were reported.</p> Conclusions <p>Adjunctive minocycline for 4 weeks showed a significant improvement in cognitive performance. However, no sustained benefits were observed beyond the treatment period.</p> Clinical Trials Registration <p>NCT06033846.</p> Graphical Abstract <p></p>