To establish whether C-reactive protein (CRP) is an independent predictor of all-cause mortality and hospitalization in chronic obstructive pulmonary disease (COPD), we followed 200 patients with COPD and 201 age- and gender -matched controls for a median time of 4.2 years (range, 0.2-5.1 years). Airflow obstruction was rated moderate if forced expiratory volume in one second (FEV(1)) was 50-69% of the predicted value, or severe if FEV(1) was <50%. The CRP level was categorized as low (≤3 mg/L) or high (>3 mg/L). The hazard of death was estimated by a proportional hazard regression model, using controls with low CRP as the reference category. Fifty subjects died: 41 (21%) among the COPD and 9 (4%) among the controls (p < 0.0001). The hazard of death in moderate COPD was not significantly higher than in the reference category, independently of the CRP level. In severe COPD with a low CRP, the hazard of death is 3.4 times higher than in the reference category (p = 0.008); in severe COPD and a high CRP it is 9.6 times higher (p < 0.0001). The rate of hospitalization in COPD patients with a high CRP is 1.9 times higher than in those with a low CRP [95% confidence interval (CI), 1.2-3.2]. In severe COPD, it is 6.9 times higher than in moderate COPD (95% CI, 3.8-12.7). A high CRP level is a significant amplifier of the risk of death only in severe COPD. The degree of airflow obstruction is a strong independent predictor of COPD-related outcomes.