The immunofluorescent localization of cross-linked fibrin (XFb) in kidneys from 87 patients with renal diseases was evaluated using a monoclonal antibody that discriminates XFb from fibrinogen and its derivatives. Glomerular deposition of XFb, along the endothelial surface and in the mesangium, was frequently observed in patients with IgA nephropathy, Henoch-Schönlein purpura nephritis (HSPN), lupus nephritis, and hemolytic uremic syndrome (HUS), which was confirmed by immunoelectron microscopy. Dual-label immunofluorescent studies showed that XFb was deposited in limited areas among the sites reactive with anti-fibrinogen antibodies; XFb was not present in the crescents, Bowman's capsule or interstitium. The localization of XFb was generally discordant with that of the platelet membrane antigen and von Willebrand factor (factor VIII-related) antigen. Subendothelial co-deposition of XFb and immunoglobulins (IgA with or without IgG) occasionally accompanying C3 was found in the glomeruli of some of the patients with IgA nephropathy and HSPN. The distribution of XFb observed by immunoelectron microscopy was similar to that of electron dense deposits. The glomerular population of monocytes/macrophages in patients with XFb deposition was similar to that of those without deposition. Urinary XFb derivatives were detected by the latex agglutination test in three of the 16 patients with glomerular XFb deposition, and in two of the 18 patients without it. These data indicate that the coagulation system is activated in the kidney of patients with IgA nephropathy, HSPN, lupus nephritis and HUS, and support the concept that glomerular fibrin deposition is associated with endothelial/subendothelial and mesangial injury. The activation of the coagulation system in IgA nephropathy and HSPN seems to be mediated by immune complexes rather than monocytes/macrophages. Determination of urinary XFb derivatives is not helpful for assessing glomerular XFb deposition.