The aim of the study was to predict the impact of flow conditions, discharges and tributaries on the water quality of Lis River using QUAL2Kw model. Calibration of the model was performed, based on data obtained in field surveys carried out in July 2004 and November 2006. Generally the model fitted quite well the experimental data. The results indicated a decrease of water quality in the downstream area of Lis River, after the confluence of Lena, Milagres and Amor tributaries, as a result of discharges of wastewaters containing degradable organics, nutrients and pathogenic organisms from cattle-raising wastewaters, domestic effluents and agricultural runoff. The water quality criteria were exceeded in these areas for dissolved oxygen, biochemical oxygen demand, total nitrogen and faecal coliforms. Water quality modelling in different scenarios showed that the impact of tributaries on the quality of Lis River water was quite negligible and mainly depends on discharges, which are responsible by an increase of almost 45, 13 and 44 % of ultimate carbonaceous biochemical oxygen demand (CBOD(u)), ammonium nitrogen and faecal coliforms, for winter simulation, and 23, 33 and 36 % for summer simulation, respectively, when compared to the real case scenario.