The solution conformations of methadone (1), isomethadone (2), and their respective HCl and Mel salts have been investigated using CD and nmr. The fact that the sign of the Cotton effect of 1 undergoes solvent-induced inversion in CH3OH (compared to hexane and CHCl3) while 2 or salts of 1 and 2 show no such change suggests that 1 exhibits a high degree of conformational mobility compared to 2. When dissolved in CD3OD, only 1 was found to undergo a rapid intramolecularly catalyzed proton exchange, thus suggesting the presence of a significant population of conformers 1a and 1c. Conformational analysis based on the C-5,6 vicinal coupling constants indicated approximately a 1:1:2 ratio of the three possible staggered conformations of 1 in CDCl3. A perturbation of this distribution occurred in CD3OD. This behavior was not observed in the case of 2 and its derivatives, and this is consistent with a much higher degree of conformational homogeneity in 2. In the case of 2, nmr analysis together with other data suggests that 2b is the predominant rotamer. It is proposed that the higher enantiomeric (-/+) analgetic potency ratio of 2 relative to 1 may in part be related to their difference in conformational flexibility. On this basis it is suggested that 2 might possess more selective action than 1 and might be worthy of investigation as a suitable alternative to 1 in the maintenance of addicts.