Several organic acids depress renal transport of p-aminohippurate (PAH). In most instances, the effects can be ascribed to competitive inhibition of PAH transport. However, the nature of the depression of PAH secretion produced by dicarboxylic acids of the Krebs cycle has not been elucidated. In studies performed on dogs, using renal clearance and extraction procedures, we found that inhibition of PAH secretion induced by α-ketoglutarate (α-KG) occurs at all tubular loads of PAH, below and above Tm. The degree of inhibition of Tmpah is proportional to the renal loads of α-KG. Furthermore, depression of PAH transport induced by α-KG is sustained, i.e. it is not readily overcome by increasing PAH levels. Administration of acetate, which in normal conditions produces striking enhancement of PAH secretion, has no effect when given simultaneously with α-KG. We conclude that inhibition is noncompetitive or mixed and that renal metabolic activity is an important factor influencing PAH secretion.