Refractory schizophrenia poses many therapeutic dilemmas. Clozapine is currently considered as the most effective medication for the treatment of refractory schizophrenia. Unfortunately, it carries serious and often life-threatening adverse effects such as agranulocitosis, hypersalivation, somnolence, weight gain, diabetes, and epileptic seizures. Various combinations of clozapine with typical and other atypical antipsychotics have been suggested to improve its efficacy and reduce its often dose-related adverse effects. We present a case of a 37-year-old patient with refractory schizophrenia who has responded well to the combination of clozapine, sodium valproate, and pipamperone. The improvement was more evident in the following symptoms: auditory hallucinations, delusions, formal thought disorder, anhedonia, and social withdrawal. The combination was well tolerated: No extrapyramidal adverse effects were noted and the patient’s full blood count was within normal limits. Pipamperone, a butyrophenone derivative, is a more selective antagonist of dopaminergic D4 receptors compared with D2 receptors and a serotoninergic 5HT-2A receptors antagonist. Thus, it shows “atypicality” and shares common characteristics with clozapine: 5HT-2A antagonism and D4 > D2 blockade selectivity. Therefore, augmentation of clozapine with pipamperone theoretically should have a synergistic effect that may provide several benefits to the patient: better antipsychotic efficacy with low risk for extrapyramidal adverse effects. This combination may also allow a decrease in clozapine dose, limiting its challenging adverse effects. To the author’s knowledge, successful treatment of refractory schizophrenia with this drug combination is reported for the first time in the literature and probably merits further research.