<b><i>Background:</i></b> Forced expiratory flow at 25 and 75% of the pulmonary volume (FEF_25-75%) might be considered as a marker of early airway obstruction. FEF_25-75% impairment might suggest earlier asthma recognition in symptomatic subjects even in the absence of other abnormal spirometry values. <b><i>Objectives:</i></b> The study was designed in order to verify whether FEF_25-75% impairment in a cohort of subjects with asthma-like symptoms could be associated with the risk of bronchial hyperresponsiveness (BHR) and with airway inflammation expressed as fractional exhaled nitric oxide (Fe<smlcap>NO</smlcap>) and eosinophil counts in induced sputum. <b><i>Methods:</i></b> Four hundred adults with a history of asthma-like symptoms (10.5% allergic) underwent spirometry, determination of BHR to methacholine (PD₂₀FEV₁), Fe<smlcap>NO</smlcap> analysis and sputum induction. FEF_25-75% <65% of predicted or <-1.64 z-score was considered abnormal. <b><i>Results:</i></b> All subjects had normal FVC, FEV₁ and FEV₁/FVC, while FEF_25-75% was abnormal in 27.5% of them. FEF_25-75% (z-score) was associated with PD₂₀FEV₁ (p < 0.001), Fe<smlcap>NO</smlcap> (p < 0.001) and sputum eosinophils (p < 0.001). Patients with abnormal FEF_25-75% showed higher levels of Fe<smlcap>NO</smlcap> and eosinophils in induced sputum than did patients with normal FEF_25-75% (p < 0.01 and p < 0.01, respectively). Subjects with abnormal FEF_25-75% had an increased probability of being BHR positive (OR = 13.38; 95% CI: 6.7-26.7; p < 0.001). <b><i>Conclusions:</i></b> Our data show that abnormal FEF_25-75% might be considered an early marker of airflow limitation associated with eosinophilic inflammation and BHR in subjects with asthma-like symptoms, indicating a role for FEF_25-75% as a predictive marker of newly diagnosed asthma.