Objective: We aimed at comparing the effectiveness of long acting β-agonist+long acting muscarinic antagonist (LABA+LAMA) versus both LABA+inhaled corticosteroid (ICS) and LAMA+ICS in non- asthmatic patients with moderate to severe COPD. In addition, we aimed at assessing the changes occur in plasma concentrations of TNF-α, fibrinogen and IL-6 with the disease activity. Methods: In this pilot study, 45 non-asthmatic patients with moderate to severe COPD were randomized into three groups; group I (LABA+ICS) received Formoterol/Budesonide, group II (LAMA+ICS) received Tiotropium/Budesonide and group III (LABA+LAMA) received Formoterol/Tiotropium for twelve weeks. The patients were assessed at baseline, four and twelve weeks after therapeutic intervention through evaluating the changes occur in FEV1 % predicted, mMRC dyspnea scale and plasma concentrations of TNF-α, fibrinogen and IL-6. Results: At baseline, the study groups were statistically similar with respect to demographic data and disease characteristics. All study therapeutic options produced an improvement in FEV1 % predicted and mMRC dyspnea scale which was associated with a reduction in plasma concentrations of the inflammatory markers. The effects produced by the three therapeutic combinations on FEV1 % predicted, plasma TNF-α, IL-6 and fibrinogen concentrations were statistically similar (four weeks after treatment; p=0.358, p=0.284, p=0.155, p=0.155 respectively) and (twelve weeks after treatment: p=0.710, p=0.773, p=0.240, p=0.076 respectively). Conclusion: In non-asthmatic patients with moderate to severe COPD, the three therapeutic combinations showed similar effectiveness. Furthermore, the results of this pilot study suggest that, inflammatory markers can be used to follow the disease activity.