Because of their elevated concentrations of plasma alpha 1-acid glycoprotein (AAG), cancer patients had a lower free fraction of methadone in plasma than did members of a control group. This difference was not great (-20%), but there was a fourfold variation in free fraction among a group of 13 patients (0.064 to 0.23). The bound/free methadone concentration ratio correlated linearly with plasma AAG. The binding of methadone to AAG was characterized by two classes of binding sites, the more avid having an association constant of 4 X 10(5)M-1 and an N of 0.38. Methadone could be displaced from AAG binding sites by a number of drugs: propranolol, chlorpromazine, prochlorperazine, thioridazine, and imipramine. The concentrations required for significant displacement (27 microM), as well as the relatively low Ka for methadone, suggest that the free fraction of methadone will not be significantly affected by elevated methadone concentrations or through displacement by other drugs that also bind to AAG.