Background &Aims: Some patients with Crohn’s disease (CD) develop antibodies against mannan, a component of the yeast Saccharomyces cerevisiae cell wall. Mannan binding lectin (MBL), a component of the innate immune system, can bind to S. cerevisiae. MBL concentration depends on genetic polymorphisms. The aim of this study was to evaluate whether low MBL contributes to anti S. cerevisiae antibody (ASCA) production. Methods: ASCA and MBL concentrations in sera from patients with CD (n = 74), ulcerative colitis (UC) (n = 22), and healthy controls (n = 32) were measured by an enzyme linked immunosorbent assay (ELISA). Genetic MBL variants were determined from 58 CD patients, 18 UC patients, and 47 controls by DNA sequencing. Lymphocytes were tested for proliferative response after stimulation with mannan. Results: ASCA were found in 47%of the patients with CD and in 0%of the controls. More ASCA positive patients (52%) had low serum MBL concentrations compared with ASCA negative patients (4%) (P <.0.0001). T cell proliferation in response to mannan stimulation was observed in ASCA positive patients and could be inhibited by the addition of MBL. These patients had significantly lower MBL serum concentrations than patients whose lymphocytes did not proliferate on mannan stimulation (P < 0.0001). Homozygous or compound heterozygous MBL mutations in the exon 1 and promoter occurred in 12 patients with cellular or humoral immune reactivity to mannan as compared with only 1 nonreactive patient (P < 0.0001). Conclusions: A subgroup of CD patients is characterized by ASCA positivity, T cell proliferation on mannan stimulation, and mutations in the MBL gene that result in MBL deficiency. Thus, we propose that enhanced mannan exposure stimulates specific immune responses in a subgroup of CD patients with genetically determined low MBL concentrations. This enhanced exposure contributes to the generation of ASCA. Background & Aims: Some patients with Crohn’s disease (CD) develop antibodies against mannan, a component of the yeast Saccharomyces cerevisiae cell wall. Mannan binding lectin (MBL), a component of the innate immune system, can bind to S. cerevisiae. MBL concentration depends on genetic polymorphisms. The aim of this study was to evaluate whether low MBL contributes to anti S. cerevisiae antibody (ASCA) production. Methods: ASCA and MBL concentrations in sera from patients with CD (n = 74), ulcerative colitis (n = 22), and healthy controls (n = 32) were measured by an enzyme linked immunosorbent assay (ELISA). Genetic MBL variants were determined from 58 CD patients, 18 UC patients, and 47 controls by DNA sequencing. Lymphocytes were tested for proliferative response after stimulation with mannan. Results: ASCA were found in 47% of the patients with CD and in 0% of the controls. More ASCA positive patients (52%) had low serum MBL concentrations compared with ASCA negative patients (4%) (P <.0.0001). T cell proliferation in response to mannan stimulation was observed in ASCA positive patients and could be inhibited by the addition of MBL. These patients had significantly lower MBL serum concentrations than patients whose lymphocytes did not proliferate on mannan stimulation (P <0.0001). Homozygous or compound heterozygous MBL mutations in the exon 1 and promoter occurred in 12 patients with cellular or humoral immune reactivity to mannan as compared with only 1 nonreactive patient (P <0.0001). Conclusions: A subgroup of CD patients is characterized by ASCA positivity, T cell proliferation on mannan stimulation, and mutations in the MBL gene that result in MBL deficiency. Thus, we propose that enhanced mannan exposure stimulates specific immune responses in a subgroup of CD patients with genetically determined low MBL concentrations. This enhanced exposure contributes to the generation of ASCA.