For a better understanding of the processes leading to diabetic microangiopathy, type IV collagen from kidneys of patients with long-term diabetes was compared with the collagen from kidneys of sex- and age-matched controls. Type IV collagen from diabetic kidneys revealed no abnormalities in amino acid composition, hydroxylation of proline and lysine, enzymatic glycosylation of hydroxylysine, and immunological reactivity with several monoclonal and polyclonal, anti-type IV collagen antibodies. However, ketoamine-linked hexose, resulting from the nonenzymatic condensation of glucose with lysyl or hydroxylysyl residues, was 1.7-fold higher in diabetic type IV collagen. The stoichiometry of this modification was estimated to be 1-2 residues of hexose per triple helical molecule (Mr 380,000). This small amount of ketoamine-linked hexose might hardly have an effect on the function and turnover of type IV collagen, unless it is bound to a crucial site along the collagen molecule. The nonenzymatic glycosylation of collagen might therefore be a mere consequence of the metabolic disturbances, rather than the primary cause for the late complications of diabetes mellitus.