The metabolism of phenacetin and N‐acetyl‐p‐aminophenol (APAP) was investigated in con;unction with studies of renal tubular cell excretion. A significant increase in renal tubular cell excretion was observed in 2 of 9 healthy volunteers receiving a total of 13.5 Gm. of phenacetin in 5 days and in 1 of 8 volunteers receiving the same dose of APAP. Following oral doses of 1.8 Gm., the maximum plasma concentrations of phenacetin varied from 1.3 to 24.8 P,g per milliliter, and there were often marked differences in the same individual during repeated studies. There was less variation in the plasma concentrations of free AP AP following administration of phenacetin or AP AP and the half‐life of both drugs in the plasma was relatively constant in a given individual. Approximately 78 per cent of the dose of phenacetin and 85 per cent of the APAP was recovered as free and con;ugated APAP in the urine in 24 hours. Many pigmented bands were observed on thin layer chromatograms of hydrolyzed urine extracts from sub;ects receiving phenacetin. In contrast, negligible amounts of pigment were present when APAP was taken. It was not possible to demonstrate differences in the absorption, excretion, or metabolism of phenacetin or AP AP in volunteers showing a marked renal tubular cell response compared with those who did not.