Some patients suffering from schizophrenia fail to respond to or tolerate adequate doses of available antipsychotic medications. Thus, innovative pharmacotherapeutic approaches, such as augmentation strategies, play an important role in the management of these treatment-resistant patients. A recent case report suggested that the administration of famotidine to a patient suffering from schizophrenia with peptic ulcer disease was associated with improvement in the deficit symptoms of schizophrenia. Famotidine is a potent highly selective H2 receptor antagonist which crosses the blood-brain barrier. Impressed by this finding, famotidine was prescribed to some of our treatment-resistant patients suffering from schizophrenia who demonstrated significant deficit symptoms of schizophrenia. The subjects were 12 (eight male, four female) treatment-resistant psychotic patients whose antipsychotic medications were augmented with famotidine in an open trial. They ranged in age from 21 to 48 years with a mean age of 32.75 years. Seven of the 12 subjects made significant improvement resulting in discharge from hospital. Paranoid disturbances as well as absence of comorbid substance use were predictors of good response to famotidine augmentation of the antipsychotic medications. The results implied that H2 receptor activity in the brain might play a role in the pathogenesis of deficit syndromes in schizophrenia. Further studies of this strategy are recommended, since it may open a window of understanding of the negative (deficit) syndrome and its treatment.