We aimed to evaluate the accuracy of baseline exhaled nitric oxide fraction (F(eNO)) to recognise individuals with difficult-to-treat asthma who have the potential to achieve control with a guideline-based stepwise strategy. 102 consecutive patients with suboptimal asthma control underwent stepwise increase in the treatment with maximal fluticasone/salmeterol combination dose for 1 month. Then, those who remained uncontrolled received oral corticosteroids for an additional month. With this approach, 53 patients (52%) gained control. Those who achieved control were more likely to have positive skin results (60.4% versus 34%; p = 0.01), positive bronchodilator test (57.1% versus 35.8%; p = 0.02) and peak expiratory flow variability > or =20% (71.1% versus 49.1%; p = 0.04). Conversely, depression was more frequent in those who remained uncontrolled (18.4 % versus 43.4 %; p = 0.01). An F(eNO) value > or =30 ppb demonstrated a sensitivity of 87.5% (95% CI 73.9-94.5%) and a specificity of 90.6% (95% CI 79.7-95.9%) for the identification of responsive asthmatics. The current results suggest that F(eNO) can identify patients with difficult-to-treat asthma and the potential to respond to high doses of inhaled corticosteroids or systemic steroids.