Host–microbe interactions often begin with colonization of mucosal surfaces. These relationships are highly specific, as certain microbial species are found only in particular microenvironments. Transcriptional microarrays were used to screen host genes whose expression in the murine nasal mucosa was affected by colonization with the Gram‐positive bacterium Streptococcus pneumoniae. Siderocalin (Scn, or lipocalin 2 or neutrophil gelatinase‐associated lipocalin) expression was increased up to 65‐fold during colonization by real‐time quantitative reverse transcription polymerase chain reaction (qRT‐PCR). Western analysis showed that Scn was secreted into airway surface fluid in colonized animals. Immunohistochemical analysis localized Scn expression primarily to secretory Bowman's glands. Similar results were observed during colonization with the Gram‐negative bacterium Haemophilus influenzae, suggesting that Scn secretion is a general response. Western analysis of human nasal secretions also demonstrated secretion of Scn at potentially bacteriostatic levels. This is a previously unrecognized response that may have a role in determining the establishment or maintenance of mucosal colonization. Scn contributes to antimicrobial defence by sequestration  of a subset of microbial siderophores. As neither S. pneumoniae nor H. influenzae are known to produce or utilize siderophores, successful colonizers of the nasal passages may have evolved siderophore‐independent mechanisms to acquire essential iron and to evade the inhibitory effects of Scn.