Carbohydrate-deficient glycoprotein syndrome (CDGS) is a newly recognized family of diseases characterized by the absence from the transferrin molecule of at least one glycan chain (type I) or an antenna of the glycan chain (type II). CDGS is currently diagnosed by studies of serum transferrin sialylation. We have developed an alternative Western blot-based method to detect serum transferrin species with reduced molecular masses due to altered glycosylation. Two additional bands are observed in type I CDGS, while a single lower band is observed in type II CDGS, relative to healthy subjects. N-glycanase treatment of serum from type I CDGS patients and normal subjects yields a single band of the same mass in the two cases, confirming that the glycan is the only moiety involved in the differential Western blot pattern. Similar results were found with serum alpha 1-acid glycoprotein, haptoglobin and alpha 1-antitrypsin. Western-blot analysis of one or more serum glycoproteins permits the differential diagnosis of CDGS.