An innovative method was developed to determine interactions between pharmaceuticals and dissolved organic matter (DOM) using solid phase extraction. DOM and DOM-associate pharmaceuticals could pass through a selected solid phase cartridge while the cartridge retained their corresponding free species in water. This method has been validated and compared the results obtained using the acceptable dialysis-membrane method. We further measured the associations of a series of pharmaceuticals commonly found in the environment with DOM using this method. The magnitudes of the interactions were ranked, and related to the specific physicochemical properties of the pharmaceuticals.