The extent of "first-pass" elimination of lidocaine in relation to the site of absorption in the rectum of rats was investigated. Male Wistar rats received lidocaine orally, i.v. or rectally at 4, 2, 1 and at about 0.2 cm from the anus. In all cases 5.0 mg of a tritium-labeled lidocaine solution was administered by zero-order infusion into the rectum. In blood, unchanged lidocaine and urine and feces total radioactivity were measured. Lidocaine was absorbed almost completely in all cases as assessed relative to i.v. administration. The average elimination half-life was about the same for all routes of administration (approximately 27 min). Systemic availability of lidocaine when given by the oral route was 16%; a similar value was found after rectal administration at 4 cm distance from the anus. At 2 cm distance from the anus the mean systemic availability was 21%, at 1 cm, 45% and as closely as possible to the anus, 72%. It is concluded that the degree of avoidance of first-pass elimination of rectally administered lidocaine is very much dependent on the site of drug administration. When the drug is absorbed very closely to the anus, little first-pass elimination occurs.