Background Evidence suggests that systemic inflammation may play an important role in the progression and morbidity of chronic obstructive pulmonary disease. It remains controversial whether inhaled corticosteroid in combination with a long-acting beta(2)-adrenoceptor agonist can attenuate systemic inflammation. We evaluated the effect of salmeterol/fluticasone propionate on circulating C-reactive protein level in stable chronic obstructive pulmonary disease patients. Methods An open-label clinical trial was conducted to recruit 122 outpatients with stable moderate-to-severe chronic obstructive pulmonary disease from department of respiratory medicine in two teaching hospitals between June 2007 and March 2008. Patients were randomized into two groups (1:1) to receive either the combination of 50 mu g salmeterol and 500 mu g fluticasone twice daily (n=61), or the combination of 206 mu g albuterol and 36 mu g ipratropium q.i.d (n=61) over 6 months. Circulating C-reactive protein concentrations were measured before randomization and during the follow-up. The efficacy of treatment was also assessed by spirometry, as well as health status and dyspnea score at baseline and after 6-month treatment. Results Baseline characteristics of two groups were similar. Compared with ipratropium/albuterol, the combination of salmeterol/fluticasone significantly reduced circulating level of C-reactive protein (-1.73 vs. 0.08 mg/L, respectively, P <0.05) after 6-month treatment. Forced expiratory volume in one second (FEV1) and health status also improved significantly in salmeterol/fluticasone group compared with ipratropium/albuterol. Salmeterol/fluticasone treatment subjects who had a decrease of circulating C-reactive protein level had a significant improvement in FEV1 and St George's Respiratory Questionnaire total scores compared with those who did not (185 vs. 83 ml and -5.71 vs. 1.79 units, respectively, both P<0.01). Conclusion Salmeterol/fluticasone treatment reduced circulating C-reactive protein concentration in clinically stable moderate-to-severe chronic obstructive pulmonary disease patients after 6-month treatment. Chin Med J 2010;123(13):1652-1657