Background: We organized this study in order to investigate differences in serum inflammatory profiles and circulating serum pneumoproteins between smokers with and without chronic obstructive pulmonary disease (COPD). Methods: Patients aged 35-70 years with COPD and a smoking history ≥10 pack-years (cases, n=38) and 38 participants with the same smoking history without COPD (controls) were included in a comparative study conducted as part of a population-based cross-sectional study with 2,388 individuals in northwestern Russia. Cases and controls were matched for age and smoking history. Airflow obstruction (AO) was defined using forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.70 and/or FEV1/FVC < lower limit of the normal cut-off values. Patients at risk for COPD were reassessed using a standardized diagnostic work-up protocol. Several parameters, among which four inflammatory biomarkers [the highsensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) levels] and two pneumoproteins [surfactant protein D (SP-D) and Clara cell secretory protein 16 (CC16)], were measured in the peripheral blood. Systemic inflammation was defined as at least 2 or more elevated biomarker levels. Results: Out of all smokers, 57.9% with normal spirometry and 36.8% with COPD did not have systemic inflammation, whereas 44.7% of the patients with COPD and 5.3% of the patients without AO demonstrated at least two elevated biomarker levels. No difference in age, gender, and smoking history, environmental and occupational exposure was found between the non-inflamed and the inflamed smokers.Of all risk factors studied, only COPD was associated with systemic inflammation [odds ratio (OR) 11.42, 95% confidence interval (CI): 2.13-58.84].Conclusions: Our study describes the systemic inflammatory network pattern associated with COPD and how it differs from the pattern in smokers with normal lung function. Systemic inflammation is not present in all smokers with COPD; in contrast, some non-obstructed smokers are characterized by systemic inflammation. From this perspective, smoking itself could be seen as a disease and studied accordingly.Trial registration: NCT02307799.