The present 16-week open-label uncontrolled trial was aimed to explore the efficacy of adjunctive agomelatine on clinical symptoms and cognitive functioning in 20 schizophrenia patients showing partial response (Brief Psychiatric Rating Scale, mean [SD] baseline total score = 37.5 [6.6]) to clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that agomelatine at a dosage of 50 mg/d was associated with score reduction in all Positive and Negative Syndrome Scale domains (positive, P = 0.011 and Cohen d = 0.7; negative, P < 0.0001 and Cohen d = 1.1; psychopathology, P = 0.001 and Cohen d = 0.9) and total score (P = 0.001, Cohen d = 1.2), depressive (Calgary Depression Scale for Schizophrenia, P = 0.013 and Cohen d = 0.6), and overall clinical symptoms (Brief Psychiatric Rating Scale, P = 0.001 and Cohen d = 0.6 ); moreover, improved performances on Stroop task (P = 0.006, Cohen d = 0.7) and Wisconsin Card Sorting Test "perseverative errors" (P = 0.033, Cohen d = 0.3) were observed. The favorable effect of agomelatine on clinical and cognitive symptoms was encouraging, and more research is needed to better identify subgroups of patients who are partially responsive to clozapine monotherapy in which agomelatine augmentation may be of benefit.