Objective Quality of life is seen as an important outcome variable for patients with schizophrenia. However, the precise definition of this construct varies and has often been used to define health-related domains. The present study sought to focus on global life satisfaction as a key subjective domain and determine its relationship with clinical variables. Method The study sample included 1437 patients with chronic schizophrenia who participated in the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study. Patients were evaluated with a comprehensive battery of assessments capturing symptoms, cognition and medication side effects, among other variables. Life satisfaction was evaluated with a global self-report item. Results Greater depressive symptoms were the most robust indicator of worse life satisfaction. Lower life satisfaction was also associated with poorer psychosocial functioning, greater symptoms of anxiety, apathy and more negative attitudes toward medication. Taken together, these variables explained 20% of the variance in life satisfaction scores. Positive symptoms and other medication side effects also negatively influenced life satisfaction scores. Conclusions These results affirm that clinical variables have an adverse effect on the overall subjective well-being of patients with schizophrenia. The relatively small amount of variance explained, though, argues for a better understanding of those other variables that contribute to life satisfaction.