The lectin pathway of complement activation is initiated by mannan-binding lectin (MBL) or the ficolins through the common MBL-associated serine protease-2 (MASP-2). Deficiency of MBL has been associated with poorer outcome in cystic fibrosis (CF). We investigated the MBL pathway further by analysis of the MASP-2 deficiency mutation (D105G) as well as MBL-2 genotypes. Concentrations and genotypes of MASP-2 and MBL in 109 CF patients were correlated to lung function and chronic infections. We describe the first CF patient homozygous for the mutation, a girl with extremely severe lung disease with no other precipitating factors. We suspect total MASP-2 dysfunction to be a major modifier of CF lung disease. However, heterozygosity for the D105G mutation of MASP-2 had no correlation to MBL pathway function or poor lung function. Lung function was higher in the MBL deficiency determining genotypes (XA/YO+YO/YO) than in the other genotypes.