Aim: To evaluate the best second-line treatments for patients with uncontrolled moderate asthma. Methods: A single-center, random study was conducted in adult patients with uncontrolled moderate asthma to evaluate the effects of add-on treatments. After add-on treatments for 4 and 12 weeks, the concentration of ex­haled nitric oxide (FeNO), average daily durnal peak expiratory flow (PEF) variability and asthma control test (ACT) score were measured. Results: 94 patients have been divided into three groups to take different add-on treatments, in tiotropium bromide group, montelukast sodium group and double-dose inhaled corticosteroid (ICS) group. After four weeks, most patients improved their symptoms and ACT scores, with lower concentration of FeNO and small PEF variability. In double-dose ICS group, almost all patients took the complete controls of asthma, compared to those in other two groups. After additional 12 weeks’ therapy, patients in all three groups nearly achieved complete controls of asthma. There were two patients with pneumonia in double-dose ICS group. Patients in double-dose ICS group had higher ACT scores, lower concentrations of FeNO and smaller PEF variabilities, but a higher risk of pneumonia, compared to those in other two groups. The differences of PEF variabilities and ACT scores between tiotropium group and double-dose ICS group were not significant. Conclusion: Tiotropium in combination with ICS plus LABA showed the similar effects with double-dose ICS plus LABA, without adverse effects, which might be the best option for optimal control of asthma. © 2015, E-Century Publishing Corporation. All Rights Reserved.