This retrospective case series examined rituximab use in four adolescents with severe PANS/PANDAS and comorbid autoimmune disease who had inadequate response to standard therapies including antibiotics, corticosteroids, IVIG, and psychotropic medications. Patients received rituximab infusions every 4–6 months. Three of four demonstrated marked clinical improvement, including two who achieved near-complete remission of neuropsychiatric symptoms; one patient improved partially with intermittent relapses. A predictable symptom recurrence around 5–6 months post-infusion suggests the need for individualized maintenance dosing. The treatment was generally well tolerated, with infection-related flares and immunosuppression-associated risks managed through multidisciplinary follow-up. Findings highlight rituximab’s potential role in refractory PANS/PANDAS with autoimmunity, supporting further controlled trials and biomarker research.