Schizophrenia is a life-shortening disease and life expectancy in patients may be 15–20 years shorter than in the general population, with increasing longevity gap over time. Premature mortality in schizophrenia-spectrum disorders is mainly due to preventable natural causes, such as cardio-vascular disease, infections, respiratory tract diseases and cancer, alongside suicide, homicide and accidents. There is a complex interplay of factors that act synergistically and cause physical morbidity to patients and subsequent mortality. Smoking, alcohol/substance abuse and sedentary life style, alongside disease-related factors, such as metabolic abnormalities and accelerating aging contribute to physical morbidity. Moreover, the symptomatology of psychosis and stigma may limit patients’ access to quality medical care. Interventions to promote physical health in those patients should be multifaceted, and should target all patient-related modifiable factors, but also should address service-related healthcare disparities. Long-term antipsychotic use (including clozapine and long-acting injectables) is associated with substantially decreased all-cause mortality, including suicide and cardiovascular mortality, in patients with schizophrenia despite the well-known cardiometabolic adverse effects of second-generation agents. Integrated care may involve co-location of physical and mental health services, liaison services, shared protocols and information sharing systems, and has emerged as a way to address the physical health needs of those patients. Interventions to address mortality in schizophrenia and related syndromes should take place as early as possible in the course of the patients’ treatment, and could be an integral component of care delivered by specialized early intervention services.