Objective: To compare the efficacy of theophylline plus salmeterol/fluticasone propionate combination product (SFC) with SFC plus placebo in asthmatic patients. Methods: In this randomized, stratified, parallel-group study, 325 patients were randomized to receive either 200 mg theophylline plus 50/250 ?g SFC or placebo tablet plus 50/250 ?g SFC twice daily for 24 weeks. Outcome variables included the level of asthma control (assessed by the Asthma Control Test) and the number of patients experiencing ?1 exacerbations during the 24-week treatment period. Testing of lung function as well as measurement of the levels of inflammatory markers in induced sputum was performed. Results: There were significantly fewer patients with ?1 asthma exacerbation in the theophylline plus SFC group (29.6%) when compared with the SFC plus placebo group (46.9%) (p = 0.004). Theophylline plus SFC improved the FEF25�75% value, which indicates enhanced small airway function, to a greater extent than SFC plus placebo (66.9 � 18.8% and 57.4 � 17.6%, respectively; p < 0.001). A significant decrease in eosinophil count and concentration of eosinophil cationic protein in induced sputum was also seen in the theophylline plus SFC group when compared with the SFC plus placebo group (4.1 � 2.2% and 6.3 � 2.7%, 63.6 � 39.5 ?g/L and 89.4 � 45.6 ?g/L, respectively; all p < 0.01). Conclusion: The combination of theophylline plus SFC may provide greater protection against asthma exacerbations, and its administration is accompanied by significant improvements in small airway function and airway inflammation.