Chronic obstructive pulmonary disease (COPD) is a rapidly growing global health problem and in the United States is now the fourth commonest cause of death. Symptomatic treatment for this disease is only modestly effective. Oxygen for hypoxemic patients and cigarette smoking cessation are the only known interventions that alter the natural history of the disease. Patients with established COPD frequently develop exacerbations, clinical episodes that are characterized by cough, sputum, and worsening dypsnea and caused mostly by infections. Exacerbations are very morbid and extraordinarily costly events that also accelerate deterioration in lung function. Hospitalization for COPD accounts for about two thirds of all health care expenditures for this disease. Antibiotics and systemic corticoteroids, common treatments for severe COPD exacerbations, are only marginally effective and their widespread use may be harmful to the patient and to society at large. Reducing the frequency of severe COPD exacerbations is very important, because even small reductions would confer large human and economic benefits. Described in this application is a proposal for two separate randomized clinical trials to determine whether low-dose theophylline or inhaled corticosteroids will reduce the frequency of severe COPD exacerbations. Once widely prescribed, theophylline has fallen into disfavor as a COPD treatment, partly due to safety issues. However, recent studies indicate that theophylline may prevent severe COPD exacerbations and that anti-inflammatory activity is retained at lower and safer doses. Recent trials suggest that inhaled corticosteroids may also prevent severe COPD exacerbations, but these findings have yet to be fully confirmed. Each of the two proposed trials will randomize about 700 patients with moderate-to-severe COPD (FEV1 < 60% predicted) in equal numbers to active drug (low-dose theophylline or inhaled corticosteroids) or placebo for a one-year period. The primary outcome variable is the first occurrence of a severe COPD exacerbation (defined as an unscheduled clinic or urgent care visit requiring systemic corticosteroid therapy or hospitalization) or death from any cause. Secondary outcomes include spirometry, several measures of health care utilization, respiratory medication use, and safety. Both trials are designed with 80% power to show a 30% reduction in severe exacerbations at a significance level of 0.05.