Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFs. Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.