l-alpha-Acetylmethadol (LAAM) was administered orally to two groups of subjects; one group received methadone, 50 mg/day, for three months previously and the other group were heroin addicts who had no prior exposure to methadone or LAAM. Plasma elimination curves for methadone, LAAM, and its metabolites, noracetylmethadol (N-LAAM) and dinoracetylmethadol (DN-LAAM), were determined after acute and chronic administration. The plasma decay curve for LAAM was biexpoenential (t1/2alpha = 6 hr; t1/2beta greater than 50 hr) following acute or chronic administration. Following chronic administration, N-LAAM and DN-LAAM plasma levels increased 5- to 10-fold. At this time, N-LAAM had a t1/2 of 31 hr and DN-LAAM had a t1/2 of greater than 100 hr. There appear to be at least two factors which determine the long duration of action of LAAM: metabolic conversion to active metabolites and tissue or plasma binding. Both methadone and LAAM may compete for plasma protein or tissue binding sites. The clinical implications of this potential drug-drug interaction are discussed.