OBJECTIVES: Chronic-Obstructive-Pulmonary-Disease (COPD) is a prevalent health condition mainly associated with smoking habit, which is considered the reason for higher healthcare resources utilization and related costs in the National health System. The aim of this study was to analyze and compare healthcare resource utilization and costs according to smoking status in patients with COPD in clinical practice in Spain. METHODS: A retrospective cohort nested case-control study was designed. Cases were current smokers, while two controls (former smokers) per case matched for age, sex, duration of COPD, and burden of comorbidity (number of diagnosis and Charlson index) were included using data from medical records. Non-institutionalized COPD, both genders, 40 years of age and older, seen consecutively over a period of 4 years before the index date and fulfilling eligibility criteria were considered eligible for analysis. Analysis used regression and general linear models with covariates to compare direct and indirect costs and resource utilization. RESULTS: A total of 930 COPD medical records were analyzed: 310 corresponding to cases (current smokers) and 630 to controls (former smokers). Mean age was 69.4 years (84.6% male). COPD was more severe in cases; Odds ratio (OR)=1.7 (95% CI 1.1;2.1), and higher percentage of current smokers had exacerbations [OR=2,7 (2.0;3.8)], with 4.2 vs. 1.7 exacerbations per year, respectively, on average (p<0.001). Smokers used more physicians visits both at primary care and specialized level, and emergency room as well. Drugs-based therapies were more common in current smokers COPD subjects. As a consequence, smokers had higher average annual healthcare costs; €3,784 (1,888) vs. €2,302 (2,451) in former smokers (p<0.001). CONCLUSIONS: COPD smoker patients had more exacerbations and higher severity of disease. Also, used more healthcare resources, particularly physicians visits and drugs-based therapies resulting in higher healthcare costs to the national health System.