Different studies have identified specific clinical characteristics of patients with obsessive-compulsive disorder (OCD) in comorbidity with schizotypal personality disorder (SPD), although no perspective evaluations of prognosis and response to treatment have been conducted so far. The aims of the present study were to evaluate: (1) the clinical and demographic correlates of OCD patients with comorbid SPD (OCD-SPD) using standardized instruments; (2) the response of OCD-SPD patients to long-term naturalistic pharmacological treatment. Socio-demographic and clinical characteristics of patients with OCD-SPD were compared to patients with “pure OCD”. OCD-SPD patients were characterized by a greater severity of obsessive-compulsive symptomatology, earlier age at onset, a higher rate of schizophrenia spectrum disorders in their first-degree relatives and a poorer insight. During the observational period, OCD-SPD patients were less likely to achieve remission of their symptomatology and required a greater number of trials with different antipsychotic drugs or received more frequently augmentation with antipsychotics. Our findings suggested that comorbidity with SPD is correlated to a poor treatment response in OCD patients and a reduced likelihood to recover from OCD symptoms, following standard pharmacological treatments. Further research is needed to identify alternative strategies for the management of this cohort of patients.