The subject of hydrocarbon inhibition of cytochrome P450-dependent reactions as well as data on other enzyme-catalyzed reactions from the literature was examined to determine the relationship between the "hydrophobicity" of the hydrocarbons and their ability to act as inhibitors. The compounds used in these studies (benzene, toluene, ethylbenzene, n-propylbenzene, and n-butylbenzene) behave as competitive inhibitors, with the affinity increasing as the size of the inhibiting hydrocarbon increases. A similarity was seen in the size dependence for both hydrocarbon inhibition of cytochrome P450-dependent activities (-0.6 to -0.7 kcal/mol/methylene group) and transfer of these compounds between aqueous and organic phases (-0.68 kcal/mol/methylene group), suggesting that the active site of cytochrome P450, in some ways, is comparable to an organic solvent in its ability to accommodate hydrophobic compounds. A more detailed examination of this process was initiated to separate the "hydrophobic effect" into its two component processes: (i) hydration of the hydrocarbon ligand and (ii) transfer of the unhydrated hydrocarbon onto the enzyme active site. In other words, do larger hydrocarbons bind more avidly to the active site because they are drawn more effectively into that site (pull), or is the size-dependent increase in hydrocarbon binding the result of the larger compounds being more efficiently expelled from the aqueous medium (push)? The results indicate that the predominant force involved in binding is the ability of the active site of cytochrome P450 and an impressive number of other enzymes to draw the hydrocarbon from the aqueous medium. The hydration of the hydrocarbon is much less dependent on the size of the hydrocarbon, indicating that dehydration or partial dehydration of the hydrocarbon molecule (upon leaving the solution and combining with the enzyme) contributes to the overall binding process to a much lesser extent; hydrophobic binding in the most widely used sense (entropy driven) is not the primary driving force that is responsible for the observed size dependence effects. It is pointed out that not all types of binding would be expected to follow the law which describes the size dependence for simple hydrocarbons because of heat-entropy relationships. The different temperature dependence of these heat-entropy relationships further complicates the analogy between enzyme-ligand binding and ligand partitioning between aqueous and organic phases. The maximum contribution that can be attributed to entropy driven hydrophobic binding (in the most widely used sense) is -0.1 to -0.2 kcal/mol/methylene group for the aromatic hydrocarbons examined here.