The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD). Bronchial lavage fluid from subjects with moderate-to-severe persistent asthma (n = 16) or COPD (n = 37), or from healthy controls (n = 18), was analysed for neutrophils, total sRAGE, endogenous secretory RAGE (esRAGE), HMGB1 and SAA. We also determined systemic levels of sRAGE in a separate group of asthmatic (n = 101) and COPD (n = 34) subjects. Subjects with neutrophilic asthma or COPD had undetectable levels of lung sRAGE, while levels of sRAGE in asthma/COPD without neutrophilia were similar to those in controls. Systemic sRAGE was significantly decreased in subjects with neutrophilic asthma or COPD compared with those without airway neutrophilia. There was significant positive correlation between total sRAGE and esRAGE in the lung and systemically. HMGB1 levels were similar in all subject groups, while SAA was below detectable levels. Neutrophilic airway inflammation in asthma and COPD is associated with reduced sRAGE.