The glycosylation features of CSF oligoclonal IgG, and possible changes in N-glycans of CSF IgG in multiple sclerosis (MS) were studied. After isoelectric focusing (IEF) of CSF, bands were detected using biotinylated lectins and avidin-horseradish peroxidase. Concanavalin A (Con A) binding showed that mannose exists throughout the pH range of oligoclonal IgG. Sambucus nigra antigen (SNA) bound acidic and neutral oligoclonal IgG only, suggesting that alkaline oligoclonal IgG is deficient in sialic acid. Deglycosylation of CSF IgG using peptide-N-glycosidase F suggested that the range of isoelectric points of oligoclonal IgG bands is not due to carbohydrate differences alone. Lectin immunoassays, whereby protein A purified IgG was captured by anti-IgG coated tubes and probed using a range of biotinylated lectins, were used to compare 13 CSF samples from MS patients with 14 control samples. With Con A binding, a significantly higher mean and larger variance was found for the MS group (t-test: P < 0.05). Con A binding correlated with CSF [IgG]/[total protein]% (r=0.390; P=0.0443). Using HPLC to separate oligosaccharides released from IgG by hydrazinolysis and labelled with 2-aminobenzamide, glycans were determined in 7 CSF samples with oligoclonal IgG, and 6 CSF samples without. The ratio of the peak for biantennary fucosylated agalactosyl glycans to total monogalactosylated glycan peaks was lower for the oligoclonal IgG samples (t-test: P=0.0141). The overall results suggested that glycosylation changes occur in CSF IgG in MS, and that oligoclonal IgG contains less sialic acid but more galactose than polyclonal IgG.