Background:Acidic inhalers can be associated with increased adverse reactions. Objectives: This study aimed to determine the acute local tolerability of acidic aqueous placebo formulations delivered via Respimat® Soft Mist™ Inhaler (SMI) and placebo chlorofluorocarbon metered dose inhaler (CFC-MDI).Methods: A single-dose (four inhalations), randomized, double-blind within Respimat SMI device, four-way crossover study in asthma patients with documented bronchial hyperresponsiveness was used. Patients received acidic placebo solutions [pH 2.7, 3.4 or 7.0 (neutral)], delivered via Respimat SMI or placebo CFC-MDI. The primary endpoint was the largest decrease in forced expiratory volume in 1 s (FEV₁) from baseline to 0–30 min after dosing. Secondary endpoints included spirometry, paradoxical bronchoconstriction (defined as a fall in FEV₁ ≧15% below baseline within 30 min of dosing), cough episodes and adverse events.Results: Thirty-two patients were included in the per-protocol population (mean age 27 years, 62.5% males). The mean percentage decrease in FEV₁ was comparable between treatment groups: –1.6% (Respimat SMI pH 2.7), –1.8% (Respimat SMI pH 7.0), –1.9% (CFC-MDI), and –2.3% (Respimat SMI pH 3.4); no patient experienced paradoxical bronchoconstriction. The mean number of cough episodes was significantly lower in the Respimat SMI pH 2.7 group versus CFC-MDI (p = 0.0165). No patient used rescue medication. Only 3 patients experienced at least one adverse event. Conclusions: The Respimat SMI pH 2.7 placebo solution does not induce adverse events in these patients. Compared with the CFC-MDI placebo suspension, Respimat SMI is a well-tolerated inhaled medication delivery system that can accommodate medication formulations with a wide range of pH solutions.