Patients with chronic obstructive pulmonary disease (COPD) have evidence of systemic inflammation that may be implicated in the development of comorbidities. To test the hypothesis that elevated levels of three inflammatory biomarkers are associated with increased risk of comorbidities in COPD. We examined 8,656 patients with COPD from two large Danish population studies and during a median 5 years' follow-up recorded hospital admissions due to major comorbidities as endpoints. We measured baseline C-reactive protein (CRP), fibrinogen, and leukocyte count, and recorded admissions due to ischemic heart disease, myocardial infarction, heart failure, type II diabetes, lung cancer, pneumonia, pulmonary embolism, hip fracture, and depression for all participants. Multifactorially adjusted risk of ischemic heart disease was increased by a factor of 2.19 (95% confidence interval, 1.48-3.23) in individuals with three biomarkers elevated (CRP > 3 mg/L, fibrinogen > 14 μmol/L, and leukocyte count > 9 × 10(9)/L) versus individuals with all three biomarkers at or below these limits. Corresponding hazard ratios were 2.32 (1.34-4.04) for myocardial infarction, 2.63 (1.71-4.04) for heart failure, 3.54 (2.03-6.19) for diabetes, 4.00 (2.12-7.54) for lung cancer, and 2.71 (2.03-3.63) for pneumonia. There were no consistent differences in risk of pulmonary embolism, hip fracture, or depression as a function of these three biomarkers. Simultaneously elevated levels of CRP, fibrinogen, and leukocyte count are associated with a two- to fourfold increased risk of major comorbidities in COPD. These biomarkers may be an additional tool for clinicians to conduct stratified management of comorbidities in COPD.