Mixed cryoglobulins (MCs) are proteins that precipitate from cooled serum, and are composed of a polyclonal immunoglobulin G (IgG) bound to another immunoglobulin that acts as an anti-IgG rheumatoid factor (RF). In type II mixed cryoglobulinemia, the antiglobulin component, usually of the IgM class, is monoclonal; it is polyclonal in type III mixed cryoglobulinemia. The majority of MCs are found in patients with connective tissue diseases, infectious or lymphoproliferative disorders, hepatobiliary diseases, or immunologically mediated glomerular diseases (secondary MCs). The etiology is not clear for 30% of all MCs, and this type of cryoglobulinemia is called "essential." There is a common clinical syndrome in types II and III essential mixed cryoglobulinemia (EMC) characterized by purpura, weakness, and arthralgia. In type II EMC only, in which an IgMk is the monoclonal RF, a membranoproliferative glomerulonephritis (MPGN) occurs with some peculiar morphologic and clinical features; this is termed "cryoglobulinemic GN." Glomerulonephritis can be differentiated from idiopathic MPGN, especially in the acute stage, which is characterized by an acute nephritic syndrome, by the following findings: (1) the presence of large deposits filling the capillary lumen that sometimes are shown to have a characteristic fibrillar or crystalloid structure by electron microscopy; (2) the extent of the exudative component consequent to the frequently massive infiltration of monocytes; (3) a more diffuse and evident thickening of the glomerular basement membrane, which has a double-contoured appearance that is mainly due to the peripheral interposition of monocytes, with less evident mesangial expansion; and (4) possibly some vasculitis in small and medium-sized renal arteries without concomitant features of segmental necrotizing GN or crescentic GN.(ABSTRACT TRUNCATED AT 250 WORDS)