Background: Schizophrenia often co-occurs with chronic medical illnesses. Beside comorbid somatic illness, somatic symptoms appear as a result of side effects of antipsychotics during treatment of psychotic disorders, which may lead to certain diagnostic problems in deciding regarding the origin of such symptoms (somatic illness vs. side effects). The aim of this article is to review literature regarding comorbidity of psychotic disorders and somatic disorders and to point at possible diagnostic problems in differentiating comorbid somatic illness from side effects of antipsychotics. Content analysis of literature: Literature research included structured searches of Medline and other publications on the subject of comorbidity of psychotic disorders and somatic disorders and possible diagnostic problems in differentiating comorbid somatic illnesses from side effects of antipsychotics. Conclusion: Co-occurrence of schizophrenia and somatic illnesses is frequent. Genetic factors, sedentary life style, poor diet, risk behaviors and smoking are some important factors that contribute to such comorbidity. Side effects of antipsychotics may cause diagnostic problems in deciding regarding the origin of such symptoms (somatic illness vs. side effects) during treatment of psychotic disorders. Bearing in mind frequent comorbidity between of psychotic and somatic disorders, early recognition of such comorbidity is important, as well as the selection of antipsychotics. It is important to recognize psychotic symptoms in patients with somatic illnesses, as well as somatic illness in patients primarily treated because of psychotic disorder.