The present 12-week open-label uncontrolled trial was aimed to explore the efficacy of reboxetine add-on pharmacotherapy on clinical symptoms and cognitive functioning in 15 patients with schizophrenia with suboptimal response (mean [SD] Brief Psychiatric Rating Scale baseline total score, 32.2 [5.4]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that reboxetine at a dosage of 4 mg/d mildly reduced only depressive symptoms (Calgary Depression Scale for Schizophrenia: P = 0.035, Cohen d = 0.7), whereas worsening of performances on phonemic fluency (P = 0.012, Cohen d = 0.5) was observed. After Bonferroni correction, changes at the Calgary Depression Scale for Schizophrenia and at the Verbal Fluency Task were not further confirmed.The results obtained indicate that reboxetine seemed to be scarcely effective for reducing clinical symptoms in patients with schizophrenia who have had an incomplete clinical response to clozapine. Regarding cognitive functioning, in our sample, a trend to experience cognitive impairment in the examined domains was observed, as confirmed by a mild worsening of performances on cognitive tasks.Schizophrenia is a heterogeneous disorder with regard to pathophysiology; therefore, data reflecting the mean response of a sample of patients may fail to reveal therapeutic effects. More research is needed to better identify subgroups of patients with peculiar features, which may account for responsivity to experimental medications and augmentation strategies.