STUDY OBJECTIVE: To clarify how mannose-binding lectin (MBL) participates in the pulmonary defense system. DESIGN: Multicenter retrospective study. PARTICIPANTS: Sixty-two patients with unexplained recurrent respiratory infections, 50 patients with nontuberculous mycobacterial infection, 23 patients with aspergillosis, and 49 patients with diffuse panbronchiolitis (DPB). For controls, 52 blood samples were provided by the Blood Donation Center of the Japanese Red Cross Society. For BAL fluid (BALF) evaluation, there were five patients with acute phase pneumonia and five healthy volunteers. MEASUREMENT AND RESULTS: We demonstrated that MBL protein could be directly measured in the BALF from the lungs of patients with pneumonia by means of enzyme-linked immunosorbent assay. Furthermore, we demonstrated that the prevalence of the codon 54 mutation of the MBL gene in 62 patients having repeated respiratory infections was significantly higher compared with healthy control subjects (54.8% vs 32.7%). The prevalence of the MBL mutant genotype among patients with DPB was higher (51.1%) than in the rest of the patients. In contrast, the prevalence of the MBL mutant genotype among patients with nontuberculous mycobacteria or Aspergillus chronic infection was not significantly different from that in control subjects (44.0% and 34.8%). CONCLUSIONS: Our results suggest that MBL may play an important role in modulating the inflammatory response against repeated microbial infections.