The aqueous activity coefficient is one of the most important parameters needed to model the behavior of a compound in aqueous media. The purpose of our study was to provide a simple means of estimating the aqueous activity coefficients for a wide range of environmentally and pharmaceutically relevant organic compounds. Experimental molar solubility and entropy of melting of 892 organic compounds was collected from WATERNT ™ v 1.0 EPA and AQUASOL databases. Experimental activity coefficient data were calculated using the experimental molar solubility (S_w), melting point (MP) and entropy of melting (ΔS_m) values. log γ _w = 1.74 - log S_w - ΔS_m(MP – 25)/(2.303*298*R) The group contribution values for calculating aqueous activity coefficient were generated by multiple regression model using SPSS (version 10.0). All other data analysis was performed using Microsoft Excel (2002). The plot for predicted versus observed aqueous activity coefficients for the entire data set of 892 compounds resulted in an R² of 0.891 and a slope of 0.999. An average absolute error in the aqueous activity coefficient determination was only 0.438 in the compounds ranging in the observed molar solubility from 10^-11 to 10⁰. This is a reasonable estimate considering the size and diversity of the compounds. This study provides a simple and accurate procedure for estimation of aqueous activity coefficients of organic compounds based solely on their chemical structure.