Many patients with persistent asthma cannot achieve the treatment goal for asthma with a single controller medication. The aim of the present study was to assess lung function and rescue medication use in asthma patients receiving four different categories of drugs in combination with an inhaled corticosteroid. Patients recruited to the study were randomized into four groups to receive budesonide with either formoterol, doxofylline, montelukast or tiotropium for a period of 3 months. Lung function (i.e. forced expiratory volume in 1 s (FEV1 )) and rescue medication use were determined at baseline and on Day 15, 30, 45, 60 and 90 of treatment. A total of 297 patients completed the study. At baseline, no significant differences (P > 0.05) were observed in any of the outcome measures. Significant within-group improvement in FEV1 was observed in all groups. On Day 90, between-group differences showed that the improvement in FEV1 was significantly (P < 0.05) higher for patients receiving budesonide + formoterol, followed by budesonide + montelukast and budesonide + doxofylline, and least for those receiving budesonide + tiotropium. Similarly, within- and between-group comparisons showed significant (P < 0.05) reductions in rescue medication use in all groups. However, the magnitude of the decrease was greater in the budesonide + formoterol group, followed by the budesonide + montelukast, budesonide + doxofylline and budesonide + tiotropium groups. Based on our findings, among the second-line treatment regimens, budesonide with either montelukast or doxofylline was found to be better than budesonide + tiotropium in patients with mild-to-moderate persistent asthma. Further studies with a longer duration are likely to be useful.