Cold, dry air (CDA) causes rhinorrhoea and nasal congestion in some individuals. This response can be mimicked in the laboratory by exposing susceptible individuals to cold, dry air nasal breathing. One of the characteristics of this response is that nasal secretions are produced by both nostrils after a unilateral challenge. This study evaluated the role of cholinergic innervation on the ipsi- and contralateral responses to unilateral CDA challenge. Twelve individuals participated in a randomized, double-blind, placebo-controlled, 3-way crossover study where local atropine and placebo were alternated ipsilateral and the contralateral to the CDA challenge. The reproducibility of the model, assessed by the response after pre-treating with placebo, was excellent; after placebo, the ipsilateral response was double the size of the contralateral. Regardless of the site of application, atropine significantly reduced the secretory response to CDA by 60-70%. However, significant secretions were still induced by CDA, even after atropine treatment. We conclude that cholinergically-mediated neuronal pathways play a major role in the nasal secretory response to CDA. Additional neuronal pathways may, however, be involved. This method is a tool to understand the different components of the mucosal response to a cold and dry environment.