We examined serum and urinary cytokeratin 19 fragment (CYFRA 21-1) levels in patients with diabetic nephropathy as a model of chronic renal failure, to investigate the mechanism of increased serum CYFRA 21-1 levels in chronic renal failure. Serum and urinary CYFRA 21-1 levels in non-insulin-dependent diabetes mellitus (NIDDM) patients with abnormal urinary immunoglobulin G (IgG) levels (>1.1 mg/g x Cr, n=126) were higher than those with normal urinary IgG levels. In NIDDM patients with normal urinary IgG levels (n=81); the urinary albumin or transferrin levels were not related to serum or urinary CYFRA 21-1 levels. We speculate that the increased serum CYFRA 21-1 levels contribute to metabolic abnormality in the kidney itself rather than the decreased urinary excretion per se, and that increased urinary CYFRA 21-1 levels are found in advanced cases of diabetic nephropathy with destruction of the size barrier.