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Quality of life (QoL) in people with schizophrenia and other serious mental illnesses (SMI) is an important outcome goal, yet there is no consistent definition of the construct. We examined three aspects of QoL in persons with SMI: overall life satisfaction, physical health-related QoL (HRQoL), and mental HRQoL. This study had two primary aims: first, to examine whether there are differences in physical and mental HRQoL in persons with SMI, and, second, to investigate the cognitive, clinical, and functional correlates of the three QoL indicators. Participants were 48 persons with SMI who completed assessments of QoL, cognition, functional capacity, psychiatric symptomatology, and medical comorbidity. Results indicate that participants experience similar levels of physical and mental HRQoL, and these two constructs are not related to one another. Physical HRQoL is associated with less medical comorbidity, while mental HRQoL is associated with negative and depressive symptoms. Overall life satisfaction was associated with fewer psychiatric symptoms and less medical comorbidity. This study adds to the important literature defining distinct domains of QoL and supports the necessity of addressing both physical and mental health factors as they relate to recovery and well-being among persons with SMI.