The development of a method for determining hydrophobicity constants for small, organic molecules by reversed-phase liquid chromatography (RPLC) is presented. The method uses capacity ratios measured at a number of different compositions of methanol to obtain derived values, denoted log k'w, upon which a new scale of hydrophobicity constants can be developed. This scale eliminates potential problems such as peak inversion that hamper RPLC methods using isocratic data to estimate hydrophobicity. The differential hydrogen bond effect observed in most correlations of RPLC data with logarithms of octanol-water partition coefficients (log Po/w) for compounds of opposite net hydrogen bonding capabilities (noncongeners) was minimized by adding trace quantities of n-decylamine and 1-octanol to the eluent and using an octyl-modified silica gel stationary phase. Values of log k'w are shown to be largely column-independent as long as the hydrophobic properties of columns are similar. The correlation of log k'w values with the logarithms of bovine serum albumin binding constants (log 1/C) is shown to be statistically indistinguishable from the correlation of log 1/C with log Po/w, indicating that this data models log 1/C as well as log Po/w for these compounds. Additionally, the chromatographic system is automatable and thus capable of higher sample throughput than measurements of log Po/w by the shake-flask method.