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OBJECTIVE: To report a case of persistent psychosis that developed during interferon alfa (IFN-α) therapy for chronic hepatitis B. CASE SUMMARY: A 26-year-old man who was diagnosed with active chronic hepatitis B began treatment with IFN-α. Five months after initiation of therapy, he developed acute psychosis with prominent persecutory delusions and auditory hallucinations. Despite discontinuation of IFN-α therapy and addition of antipsychotic drug treatment, only partial recovery from psychosis was observed after 4 months of hospitalization. DISCUSSION: Unlike many previously reported cases, this patient showed only partial recovery from psychosis, despite the discontinuation of IFN therapy. Except for receiving a relatively high dose of IFN-α (10 million units 3 times/wk), the patient did not have any previously proposed risk factors for developing psychiatric adverse effects. The Naranjo probability scale indicates a probable relationship between the acute psychosis and IFN therapy. CONCLUSIONS: Despite its rare occurrence, psychosis can emerge during IFN-α therapy. This adverse effect may persist for several months, even after appropriate medical management. IFN-α should be used with careful monitoring of patients' psychiatric status during all stages of therapy.