Volatile anesthetics are uncharged dipolar molecules with hydrophobic and hydrophilic groups. Due to amphiphilicity, these molecules reside at the water-macromolecule interfaces. The extent of penetration into the hydrophobic core of macromolecules has not been established. This study measured the residence site of halothane molecules in sodium dodecyl sulfate (SDS) micelles by F-19 and H-1 NMR. The proton peaks of SDS in the frequency domain shift by micellization. The change in the chemical shift, Delta delta, by micellization varies with the position of the proton. The values for methyl, -(CH2)(9)-, beta, and alpha protons were respectively -7.04, -6.02, -1.62, and +4.96 ppm. Addition of halothane to micelles dose-dependently shifted all proton peaks of SDS to a lower magnetic field. The plot between Delta delta(hal) (delta(micelle) - delta(halothane)) and halothane concentration consisted of two linear parts with a break at the halothane/SDS mole ratio of 0.5. The nuclear Overhauser effect, NOE, was estimated by (1) irradiating with halothane F-19 and measuring SDS proton signals, H-1{F-19}, and (2) irradiating with proton signals of alpha and beta protons and measuring F-19, F-19{H-1}. It was found that halothane effects were confined to the alpha and beta positions. The decoupled signal of the halothane proton in H-1{F-19} NOE was a single peak when the halothane/SDS mole ratio was below 0.5. Above this ratio, a shoulder appeared. Gaussian deconvolution showed that 60% of the total halothane molecules in the micelle were restricted to the alpha position and 40% to the beta position at saturating halothane concentrations. Halothane did not penetrate into the hydrophobic core. At clinical concentrations, halothane molecules stayed at the outermost layer Of hydrocarbons.