Rationale:Recurrent herpes simplex encephalitis (HSE) can easily induce autoimmune encephalitis (AE). However, there are few reports of anti-contactin-associated protein-2 (CASPR2)-related encephalitis, especially with positive anti-aquaporin 4 (AQP4) antibodies.Patient concerns:A 14-year-old boy was admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University for “headache, dizziness, and fever for four days” with positive anti-CASPR2 and anti-AQP4 antibodies in the cerebrospinal fluid.Diagnoses:Cranial MRI showed lesions in the right hippocampus, amygdala, and insular lobe, with local sulcus enhancement in the right insular, temporal, and frontal lobes. The fluid-attenuated inversion recovery was significantly enhanced. Human herpes virus type I was detected by cerebrospinal fluid metagenomic testing. The patient was diagnosed with AE secondary to HSE, with positive anti-CASPR2 and anti-AQP4 antibodies.Interventions:After 2 weeks of immunoglobulin and methylprednisolone immunomodulatory therapy, acyclovir antivirus, mannitol dehydration, reducing intracranial pressure, and other symptomatic support therapy.Outcomes:The patient’s symptoms significantly improved, with no complaints of discomfort, and he was discharged for observation. The patient was followed up a month after discharge and had no complaints of discomfort.Lessons:CASPR2 and anti-aquaporin-4 antibody-positive AE have not been reported to be positive. This case will raise awareness of CASPR2 and anti-aquaporin-4 antibody-positive AE secondary to HSE, strengthen diagnostic capacities, and provide advice to treat it.