Abstarct: Sulfur is the most important impurity in iron concentrate of Sangan mine, which its excess amount affects the quality of the concentrate and is caused many problems in the production of pellets and environmental issues. Thus, the purpose of present research is to reduce sulfur and improve the flotation efficiency of iron in Sangan mine. For achieving these goals, firstly, the influential parameters on the sulfur grade and the separation efficiency of iron were identified. Then, evaluation, modeling and optimization of parameters were carried out by using response surface methodology baxsed on central composite design. In this regard, two quadratic mathematical models with high R2 values were suggested for the relationship between influential parameters with sulfur grade and separation efficiency of iron. The results indicated that the sulfur grade and the separation efficiency of iron were strongly depended by the interaction effects between parameters. Also, the concentration of collector and the interactive impact of pH with MIBC frother had the most influence on the reduction of sulfur grade and the improvement of the separation efficiency of iron. The optimization of parameters was performed using Design Expert software and the desirability function approach to obtain the highest separation efficiency of iron and the lowest grade of sulfur and the desirable values of parameters were achieved in the pH value of 7, collector concentration of 135 g/t, frother concentration of 60 g/t and conditioning time of 10 min. Under this condition, sulfur grade and separation efficiency was 0.305 and 65.4, respectively.