Three different approaches have been used to evaluate the catabolism of rabbit serum interferon (IFN) by the kidneys. Firstly, in normal rabbits the disappearance of exogenous IFN from plasma was very rapid, whereas it was significantly slower after bilateral nephrectomy. Secondly, the IFN level in arterial blood was always higher than in renal venous blood: the mean renal extraction rate of IFN in the rabbit, with a renal plasma flow of 9 ml/min, was about 1 ml/min. Thirdly, a selective and reversible tubular damage induced by maleate before intravenous administration of IFN significantly inhibited luminal uptake of IFN and markedly increases the interferonuria. All of these results support the view that the kidneys have a preponderant role in IFN filtration, catabolism and excretion.