Chronic obstructive pulmonary disease (COPD) remains a leading cause of disability and death in the United States. The identification and amelioration of systemic manifestations of COPD may improve long-term outcomes, including survival. These systemic manifestations often correlate with increased risk of mortality and may be considered surrogates of disease severity. Several potential clinical surrogates are evaluated, including airflow obstruction, dyspnea, malnutrition, hypoxemia, exercise capacity, lung hyperinflation, and anemia. The evidence in support of the impact of various COPD treatment modalities on systemic manifestations of COPD is also reviewed. Finally, the usefulness of measuring body mass index, degree of airflow obstruction, dyspnea, and exercise capacity in combination (the BODE index), as a measure of disease severity and mortality risk in COPD, is examined and found to be a simple-to-use tool for predicting COPD-related hospitalization and mortality.