Plasma and urine concentrations of factor XIII and its circulating substrates (fibronectin, fibrinogen, and alpha 2-antiplasmin) were measured in a group of 36 patients with nephrotic syndrome. The results were compared with those obtained in a group of 32 normal volunteers (control group) and 12 patients with end-stage renal disease (ESRD). A mild but significant reduction in plasma level and an abnormal urinary excretion of alpha 2-antiplasmin was found in the nephrotic group. Plasma concentrations of factor XIII, fibronectin, and fibrinogen were significantly elevated in patients with nephrosis. In contrast, patients with ESRD showed no significant difference in the plasma concentrations of either factor XIII, fibronectin, or alpha 2-antiplasmin and only a modest elevation of fibrinogen when compared with normal controls. No significant correlation was found between serum creatinine concentration and plasma levels of factor XIII and its circulating substrates in the nephrotic group. No measurable quantities of factor XIII and only small quantities of fibronectin were found in the urine of patients with nephrosis. Elevation of plasma factor XIII, fibronectin, and fibrinogen concentrations in the nephrotic group is considered to be the result of a combination of increased synthesis and possibly contracted intravascular distribution of these macromolecular proteins in the face of their negligible urinary losses. The presence of the observed abnormalities in the nephrotic group and their absence in the non-nephrotic ESRD group tends to exclude renal failure as a cause of these abnormalities. Although the clinical significance of these abnormalities is uncertain, they can potentially contribute to the thrombophilic diathesis and platelet hyperaggregability in nephrotic syndrome.