Several clinical studies have shown a large number of mental symptoms by immunomodulatory treatment with interferon (IFN). The most frequently described symptoms are depression, suicidal behaviour, manic symptoms, anxiety, psychosis and delirium, associated with other non-specific symptoms such as fatigue, irritability, psychomotor retardation, decreased libido, insomnia, difficulty in concentration and attention. Having a history of mental disorder contraindicates the use of IFN-alpha. These adverse effects that affect the mental state appear usually at the beginning of the treatment (most after 3 weeks of treatment). The incidence of psychotic episodes is low and the episodes usually remit when treatment is interrupted; only some cases require antipsychotic treatment. We present the case of a patient affected with hepatitis C who began to present self-referential delirious symptoms after receiving the treatment with IFN and who was successfully treated with paliperidone. This patient could be classified within the group of high-risk psychiatric patients given the family history of schizophrenia and his personal history of illegal drug consumption. The pharmacological actions of paliperidone are similar to other high potency atypical antipsychotics. The receptor-binding profile of paliperidone most closely resembles that of risperidone and ziprasidone. Paliperidone differs from risperidone and most other antipsychotics by its relatively low extent of enzymatic hepatic metabolism. To the best of our knowledge, this is the first case described that was successfully treated with paliperidone.