We aim to improve knowledge on risk factors that relate to mortality in subjects with exacerbation of chronic obstructive pulmonary disease (COPD) who are hospitalized in General Medicine departments. In a cross-sectional multicenter study, by means of a logistic regression analysis, we assessed the possible association of death during hospitalization with the following groups of variables of participating patients: sociodemographic features, treatment received prior to admission and during hospitalization, COPD-related clinical features recorded prior to admission, comorbidity diagnosed prior to admission, clinical data recorded during hospitalization, laboratory results recorded during hospitalization, and electrocardiographic findings recorded during hospitalization. A total of 398 patients was included; 353 (88.7%) were male, and the median age of the patients was 75 years. Of these patients, 21 (5.3%) died during hospitalization. Only 270 (67.8%) received inhaled β(2) agonists during hospitalization, while 162 (40.7%) received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The median of predicted FEV(1) prior to admission was 42%. A total of 350 patients (87.9%) had been diagnosed with two or more comorbid conditions prior to admission. An association was found between increased risk of death during hospitalization and the previous diagnoses of pneumonia, coronary heart disease, and stroke. In conclusion, comorbidity is an important contributor to mortality among patients hospitalized in General Medicine departments because of COPD exacerbation.