To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCpo of lignocaine by 100-140%. This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl X H2O orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 +/- 58 s.d.% (P less than 0.005); it increased the peak plasma lignocaine concentration by 79 +/- 50 s.d.% (P less than 0.025) and it prolonged the elimination half-life of lignocaine by 20 +/- 13 s.d.% (P less than 0.05). Propranolol treatment lowered indocyanine green clearance by 11 +/- 15 s.d.%, but this change was not significant statistically. These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.