Background: Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease and C-reactive protein (CRP) and fibrinogen are considered as main systemic inflammatory biomarkers. This study aimed to evaluate the alterations of CRP and serum fibrinogen levels in COPD patients and their correlation with the severity of disease, arterial O2 saturation and opium or cigarette consumption. Materials and Methods: This was a descriptive case-control study conducted on 31 COPD patients and 29 healthy controls selected by using easy sampling method in Afzalipour Hospital. Serum levels of CRP and fibrinogen were measured by ELISA method and analyzed using SPSS software version 15. Results: The mean serum level of CRP in the understudy patients (13.15±13.72 mg/L) was significantly higher than that of the controls (3.53±1.12 mg/L)(P=0.000). However, no significant difference was found in the mean serum level of fibrinogen between cases (3.81±0.93 mg/dl) and controls (3.72±0.9 mg/dl)(p=0.82). Also, no significant correlation was detected between the serum level of CRP or fibrinogen and severity of the disease (P=0.92 and P=0.58, respectively). A statistically significant relationship was found between the serum levels of CRP and fibrinogen and arterial O2 saturation (P=0.02). There was no significant difference in the serum levels of CRP and fibrinogen between the opium users (p=0.19) and other patients (p=0.15). Conclusion: According to our study results, COPD, per se, can increase the inflammatory biomarkers including CRP. Raised serum level of CRP is indicative of systemic inflammation which results in extra-pulmonary manifestations like cardiovascular diseases, cerebrovascular accidents, osteoporosis, and cachexia. Therefore, with routine measurement of this marker, we can evaluate the severity of systemic inflammation in these patients and choose the best treatment accordingly. (Tanaffos 2010; 9(1): 28-33)