Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Methods: Thirty-four patients received three of five treatments: FPS 100/50μg once daily (QD), FPS 100/50μg twice daily (BID), FPS 250/50μg BID, FPS 500/50μg BID, or placebo, each for 2 wk separated by 14-day washout. FeNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards Results: FPS treatments decreased FeNO compared with placebo, with largest differentiation between doses noted on day 14; mean decreases from days 1 to 14 ranged from -46.6% to -64.5% with FPS vs. -9.1% with placebo. Linear regression anal. revealed significant slopes between FPS doses, with steepest between 100/50μg QD and 100/50μg BID (-0.0039, p = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80-1.25 and 0.67-1.50 bioequivalence limits, resp.). However, as slope between BID FPS doses was shallow, a larger SS may be needed if only approved dose regimen was used. Conclusion: FeNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable.