Water quality of the Zayandehrud River, located in an arid region of central part of Iran, was assessed using National Sanitation Foundation Water Quality Index (NSF WQI) calculated by four aggregation methods. Water samples were collected monthly (July 2006 to June 2007) from eight stations in the middle of the river. The parameters required for the NSF WQI calculations including saturation percent of dissolved oxygen, biochemical oxygen demand, fecal coliforms, pH, nitrate, total phosphate, temperature deviation, total dissolved solids and turbidity were measured. According to WQIm which appeared to be more adapted to environmental conditions of the Zayandehrud River, the studied section of the river was considered as “reasonable” to “polluted” water quality. All of the calculated water quality indices showed the lowest values in August. In addition to BOD5 and fecal coliform amounts which were generally high, nitrate and total phosphate concentrations were also considerably increased due to agriculture practices in August. Generally, BOD5 and fecal coliforms are the main water quality subindices that reflect the effect of anthropogenic activities on the water quality of this river.