Abstract About 75% of patients with IRAK-4 or MyD88 deficiency develop overwhelming infections caused by S. pneumonia or S. aureus in early childhood. While IgG production is not compromised, TLR signaling mediated by IRAK-4 and MyD88 has broad effects upon the immune system, including stimulation of T-independent IgM antibody. In fact, it has recently been shown that IRAK-4/MyD88 deficiency reduces a putative reservoir of IgM production, circulating CD27+, IgD+, IgM+ B cells. Using an array of 610 glycans covering diverse structures (functionalglycomics.org), we measured serum IgM binding glycans from 8 age-matched control, 8 IRAK-4-deficient, and 3 MyD88-deficient patients. Serum IgM from these patients bound a significantly reduced number of glycans relative to controls (p < 0.05). Using a microbial glycan database (csdb.glycoscience.ru) we found that control IgM bound 18 glycans expressed by S. pneumonia or S. aureus, while IgM from IRAK-4/MyD88-deficient subjects bound only 1. The reduced recognition of glycans by IgM in IRAK-4/MyD88-deficient patients was supported by ELISA, with significant reduction in IgM binding S. pneumonia capsular glycans (p = 0.004), cell wall glycan (p <0.05), and phosphorylcholine (p <0.05), as well as S. aureus teichoic acid (p < 0.0001). These results indicate that IRAK-4/MyD88 deficiency impairs IgM recognition of glycans expressed by S. pneumonia and S. aureus, providing an explanation for heightened susceptibility to these encapsulated pathogens.