The effect of indomethacin on protein excretion and on the synthesis of glomerular basement membrane (GBM) was studied during various stages of nephrotoxic nephritis (NTN) in the rat. Daily administration of indomethacin (4 mg/kg) was instituted 1, 6, or 21 days after the induction of NTN with 210, 240, or 268 microgram kidney-fixing antibodies (KFAb). Proteinuria in rats with nephritis induced by 210 microgram KFAb decreased under treatment with indomethacin regardless of the day on which treatment was started but was not affected by indomethacin in rats with clinically more severe nephritis induced with higher doses of KFAb. GBM synthesis was measured in vivo and in vitro by determination of the incorporation of 3H-proline into the GBM. NTN rats treated with indomethacin showed increased GBM synthesis early in the course of NTN, over and above an already increased synthesis. In the later phase of NTN indomethacin treatment did not affect GBM synthesis. The absence of a relationship between the effect of indomethacin on proteinuria and its effect on GBM synthesis clearly shows that the reduction of protein excretion occurring under indomethacin treatment is not mediated by alterations in the rate of GBM synthesis.