Obsessive-compulsive disorder (OCD) is often the anxiety disorder that affects approximately 2% of the population. This disorder is associated with significant morbidity and dysfunction, and is included in the World Health Organization list of the ten most disabling medical illnesses. The therapeutic response of patients with OCD is relatively poor compared with that of other mental disorders. Pharmacological interventions for OCD have focused on modulating primarily serotonin function and secondarily dopamine neurotransmission. Augmentation treatment has been the subject of several studies in treatment-resistant obsessive compulsive disorder (OCD). We hypothesized that medications with a dual action on the melatoninergic and serotoninergic systems may be of use in treatment-resistant OCD. In this open label study we investigated the efficacy and safety of agomelatine augmentation in treatment-resistant OCD. Twelve patients, aged 18-50, fulfilling OCD criteria, having failed to respond to adequate treatment with a Serotonine Reuptake Inhibitor for at least 16 weeks, were assigned to receive agomelatine augmentation. Subjects were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and were screened for treatment-emergent side effects at baseline and week 16 of treatment. We excluded patients with comorbid psychopathology, serious medical comorbidity, current or past history of substance abuse and severe personality disorders as well as patients receiving psychotherapy in addition to psychopharmacological treatment. Agomelatine augmentation lead to net improvement in Y-BOCS and its obsession and compulsion subscales after 16 weeks of treatment (all p<0.005). Agomelatine augmentation was well-tolerated and none of the patients dropped-out. Treatment-related adverse events were recorded as follows: (n, %): nausea: 1 (8.3%), headache 4 (33.3%), dizziness: 3 (25%) and somnolence: 2 (16.7%). The present case series study has several limitations due to its open-label design and the absence of a placebo or active control group. The small number of patients further limits the impact of our findings. The present case series study showed that a 16 week add-on treatment with agomelatine, achieved on average a 25% improvement in Y-BOCS in refractory to treatment OCD patients; side effects were mild, and none of the patients dropped out throughout the 16-week study period. Agomelatine could be efficacious and well tolerated as an augmenting agent in refractory to treatment OCD. The unique pharmacological profile of agomelatine and its dual action on serotoninergic and melatoninergic receptors may be of interest in this difficult-to-treat illness. Further controlled studies are warranted to explore the efficacy of agomelatine, as well as the potential role of circadian rhythm modulation both in the pathophysiology and treatment of OCD.