1 The oxidative O-de-ethylation and aromatic 2-hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. 2 The EM group excreted in the urine significantly more paracetamol (EM: 40.8 + 14.9% dose/0-8 h; PM: 29.2 + 8.7% dose/0-8 h, 2P < 0.05) and significantly less 2-hydroxylated metabolites (EM: 4.7 + 2.3% dose/0-8 h; PM: 9.7 + 3.5% dose/0-8 h, 2P < 0.005) than the PM group.3 Apparent first-order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (km,1) were higher in the EM group (EM: k = 0.191 + 0.151 h-'; km, = 0.091 + 0.025 h-'; PM: k = 0.098 ± 0.035 h-', 2P < 0.05, km, = 0.052 + 0.019 h-', 2P < 0.05) than the PM group. The apparent first-order rate constant for 2-hydroxylation displayed no significant inter-phenotype differences. 4 Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter-individual variability in phenacetin disposition encountered in this study.