Although exacerbation of chronic obstructive pulmonary disease (COPD) is important in terms of health and costs, there is little information about which are the risk factors. We estimated the association between modifiable and nonmodifiable potential risk factors of exacerbation and the admission for a COPD exacerbation, using a case-control approach. Cases were recruited among admissions for COPD exacerbation during 1 yr in four tertiary hospitals of the Barcelona area. Control subjects were recruited from hospital's register of discharges, having coincided with the referent case in a previous COPD admission but being clinically stable when the referent case was hospitalized. All patients completed a questionnaire and performed spirometry, blood gases, and physical examination. Information about potential risk factors was collected, including variables related to clinical status, characteristics of medical care, medical prescriptions, adherence to medication, lifestyle, quality of life, and social support. A total of 86 cases and 86 control subjects were included, mean age 69 yr, mean FEV(1) 39% of predicted. Multivariate logistic regression showed the following risk (or protective) factors of COPD hospitalization: three or more COPD admissions in the previous year (odds ratio [OR] 6.21, p = 0.008); FEV(1) (OR 0.96 per percentual unit, p < 0.0005); underprescription of long-term oxygen therapy (LTOT) (OR 22.64, p = 0.007); and current smoking (OR 0.30, p = 0.022). Among a wide range of potential risk factors we have found that only previous admissions, lower FEV(1), and underprescription of LTOT are independently associated with a higher risk of admission for a COPD exacerbation.