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Background: Comorbidities are very common in chronic obstructive pulmonary disease (COPD), contributing to the overall severity of the disease. The relative prevalence of comorbidities in COPD caused by biomass smoke (B-COPD), compared with COPD related to tobacco (T-COPD), is not well known. Objectives: To establish if both types of COPD are associated with a different risk for several major comorbidities. Method: The prevalence of comorbidities was compared in 863 subjects with B-COPD (n = 179, 20.7%) or T-COPD (n = 684, 79.2%). Multivariate analysis was carried out to explore the independent relationship between comorbidities and type of exposure. Results: Three comorbidities were more frequent in T-COPD than in B-COPD: ischemic heart disease (11.5 vs. 5.0%, respectively, p = 0.01), peripheral vascular disease (9.2 vs. 2.7%, p = 0.006), and peptic ulcer disease (4.8% vs. 0, p = 0.005). After correcting for potential confounding variables, the risk of ischemic heart disease was lower in B-COPD than in T-COPD (OR: 0.33, 95% CI: 0.16-0.69, p = 0.003). Conclusions: The prevalence of ischemic heart disease is significantly lower in B-COPD than in T-COPD, suggesting a different systemic effect of both types of smoke in COPD patients.