According to the Water Framework Directive 2000/60/EC, nonylphenol (NP) has been included in the list of priority hazardous substances and subject to cessation or phasing out of discharges, emissions and losses within an appropriate timetable not exceeding 20 years. The present work analyzed monitoring data on NP and its precursors (mono- and di-ethoxylates, nonylphenol-mono-ethoxylate and nonylphenol-di-ethoxylate) collected in a highly impacted river basin in Northern Italy in order to assess the effectiveness of the adopted measures for NP reduction, during two monitoring campaigns in 2003/04 and 2009/10, respectively, before and after the entry into operation of three new wastewater treatment plants (WWTPs) in Milan. The River Lambro is the main source of pollutants also for the River Po and the Adriatic Sea. Data collected in the present work showed that in the last 7 years the reduction of the different analytes was from 70% to 90%. Most of the reduction can be attributed to the substitution of nonylphenolethoxylates in industrial uses as demonstrated by a survey in the textile industrial district. The entry into operation of the new municipal WWTPs in Milan contributes about 10% of the reduction of the total NP load discharged by the River Lambro.