This study investigated the effects of organic and colloidal fouling on the removal of a representative micropollutant sulfamethoxazole by two commercially available NF membranes. Alginate, bovine serum albumin, and colloidal silica were selected as model foulants to simulate hydrophilic and hydrophobic organic fractions, and colloidal matter that are often found in treated effluent and surface water. Membrane fouling was related to the membrane and foulant characteristics and subsequently the separation behaviour of the micropollutant sulfamethoxazole under different solution pH. On the basis of these results, it was confirmed that membrane fouling is strongly dependent on both the foulant and membrane characteristics. The complex relationship among retention mechanisms, fouling mechanisms, and the effects of fouling on retention was systematically delineated. Of the three model foulants selected for this study, colloidal fouling resulted in the most significant reduction in retention of sulfamethoxazole as well as inorganic salts, while flux decline as a result of colloidal fouling was quite moderate. Reduction in retention caused by fouling was attributed to a phenomenon known as cake-enhance concentration polarization, which was a predominant mechanism of colloidal fouling. In addition, the reported results suggested that the effect of fouling on retention is also membrane pore size dependent.