SMZ (sulfamethoxazole), as a representative of sulfonamide antibiotics, is recognized as an emerging organic micro-pollutant. It is frequently detected in the secondary effluent of wastewater treatment plants, posing potential risks to water reuse.For the advanced treatment of secondary effluent, where the removal efficiency and mechanisms of SMZ in secondary effluent by a combined slow filtration-NF (nanofiltration) process under different organic matter concentrations were investigated. The influence of microbial community structure on SMZ removal efficiency was revealed, and the mitigation mechanisms of slow filtration on membrane fouling were systematically analyzed. Additionally, the interfacial interaction mechanisms between organic pollutants of varying concentrations and the NF membrane surface were clarified.The results demonstrate that, compared to direct NF and slow filtration-NF without biofilm, the biofilm-assisted slow filtration-NF process achieves the highest removal efficiency for both SMZ and DOC (dissolved organic carbon) in water. In the biofilm formed on the slow filtration surface, Proteobacteria, Acidobacteria, Planctomycetes, Stenotrophomonas, Dokdonella, and Nitrospira are found to be the dominant microbial taxa, all of which contribute positively to SMZ degradation. The biofilm-assisted slow filtration-NF process maintains an SMZ removal rate of over 90% under varying CODcr (dichromate oxidizability) concentrations, indicating that changes in organic matter concentration have minimal influence on SMZ removal by the combined process. At neutral pH, higher organic matter concentrations lead to more severe membrane fouling, a decrease in total interfacial interaction energy, and a reduction in repulsive energy barriers, with the process being dominated by polar and electrostatic interactions. In conclusion, controlling organic matter concentration is crucial for optimizing SMZ removal and preventing membrane fouling in the biofilm-assisted slow filtration-NF combined process.