Nanofiltration (NF) of seventeen pharmaceutically active (PhAC) and endocrine disrupting compounds (EDCs), representing a wide range of physicochemical properties, was investigated using both laboratory-prepared (Milli Q (R)) and natural waters. While previous studies have probed compound removal by membranes pre-fouled with model foulants, and the impact of natural water colloidal materials, this study examined the impact of compound interactions with key organic matter fraction(s), in the absence of colloidal and suspended particles. Lake Ontario water, a Great Lakes' source of drinking water, was pretreated using ultrafiltration to remove colloidal particles but retain organic matter. Additionally, the concentration of cations in the water matrix was varied. Experiments were conducted at a recovery (50%) comparable to a full-scale system. PhAC/EDC rejection from Milli Q (R) water increased as a function of molecular weight and molecular volume, but significantly decreased with increasing compound hydrophobicity. Dissolved organic matter (DOM) fractions were found to interact preferentially with neutral PhAC/EDCs, causing increased rejection, presumably due to enhanced size exclusion of compound-humic substance (HS) pseudo-complexes arising from dipole-dipole interactions. Increased cation concentration resulted in decreased removal of the neutral compounds; presumably due to reduced HS interaction sites. The rejection of specific ionic compounds was influenced by both size and charge effects of the compound-HS complexes. (C) 2013 Elsevier B.V. All rights reserved.