The design of a water quality monitoring network is considered as the main component of water quality management including selection of the water quality variables, location of sampling stations and determination of sampling frequencies. In this study, an entropy-based approach is presented for design of an on-line water quality monitoring network for the Karoon River, which is the largest and the most important river in Iran. In the proposed algorithm of design, the number and location of sampling sites and sampling frequencies are determined by minimizing the redundant information, which is quantified using the entropy theory. A water quality simulation model is also used to generate the time series of the concentration of water quality variables at some potential sites along the river. As several water quality variables are usually considered in the design of water quality monitoring networks, the pair-wise comparison is used to combine the spatial and temporal frequencies calculated for each water quality variable. After selecting the sampling frequencies, different components of a comprehensive monitoring system such as data acquisition, transmission and processing are designed for the study area, and technical characteristics of the on-line and off-line monitoring equipment are presented. Finally, the assessment for the human resources needs, as well as training and quality assurance programs are presented considering the existing resources in the study area. The results show that the proposed approach can be effectively used for the optimal design of the river monitoring systems.