BACKGROUND: Asthma is the most common chronic inflammatory disease of the pulmonary system. The prevalence of asthma is growing enormously worldwide posing a significant health and economic burden. Asthma treatment guidelines recommend a combination of inhaled corticosteroid (ICS) and long-acting beta 2 agonist (LABA). However, there is little guidance for clinicians on selecting a specific ICS/LABA combination. AIM: The aim of the study is to compare the effectiveness of three fixed dose ICS/LABA combination therapies, i.e. fluticasone/salmeterol, fluticasone/formoterol, and budesonide/formoterol for the management of moderate-to-severe asthma. DESIGN: This was a prospective interventional, three-armed, parallel group, open label, and randomized clinical trial METHODS: Adult asthmatic patients of both genders (n = 135) were randomly allocated to the three ICS/LABA treatment groups: fluticasone/salmeterol-treated group (n = 45), fluticasone/formoterol-treated group (n = 45) and budesonide/formoterol-treated group (n = 45). All groups were treated for 3 months. The main outcome parameters included lung function (forced expiratory volume in 1 s [FEV1], FEV1%, FEV1/forced vital capacity [FVC]), inflammatory state (high sensitivity C-reactive protein [hs-CRP], eosinophilic cationic protein [ECP]) and asthma control test (ACT). RESULTS: After 3 months of treatment, fluticasone/formoterol significantly increased FEV1 compared to fluticasone/salmeterol (p < 0.01) and FEV1% compared to budesonide/formoterol (p < 0.01). Both fluticasone-containing combinations significantly increased FEV1/FVC (p < 0.001, p < 0.001), decreased serum hs-CRP (p < 0.01, p < 0.001), and serum ECP (p < 0.05, p < 0.001) and improved ACT (p < 0.05, p < 0.01) compared to budesonide. Fluticasone/formoterol significantly reduced ECP in comparison to fluticasone/salmeterol (p < 0.05). CONCLUSION: Our study showed a superiority for fluticasone-containing combinations over budesonide for the treatment of moderate to severe asthma. Within the former combinations, fluticasone/formoterol was better than fluticasone/salmeterol.