The structural features of general anesthetic binding sites on proteins are being examined using a defined model system consisting of a four–α-helix bundle scaffold with a hydrophobic core. Previous work suggested that halothane binding to the four–α-helix bundle was improved by (1) introducing a cavity into the hydrophobic core and (2) substituting a methionine side-chain in place of an α-helical heptad e position leucine. In this study, the ability of the general anesthetics chloroform and 2,2,2-trichloroethanol to bind to the hydrophobic core of the four–α-helix bundle (Aα₂-L38M)₂ is explored. The halogenated alkane chloroform binds with a dissociation constant (K_d) = 1.4 ± 0.2 mM, whereas 2,2,2-trichloroethanol binds with a K_d = 19.5 ± 1.2 mM. The affinity of both general anesthetics for the hydrophobic core of the four–α-helix bundle approximates their whole animal effective concentration in 50% of test subjects' (EC₅₀) values, as shown previously for halothane. Tryptophan phosphorescence decay rates at 77 K are accelerated by a factor of 4.5 by both bound halothane and chloroform, indicating that the heavy-atom effect is responsible for a portion of the observed fluorescence quenching. Because heavy-atom effects are operative only at short distances, the findings indicate that these general anesthetics are binding in the vicinity of the indole rings of W15 in the hydrophobic core of the four–α-helix bundle scaffold. The results indicate that chloroform, halothane and 2,2,2-trichloroethanol may occupy the same sites on protein targets.