Combine header loss comprises more than 50% of wheat harvesting losses. Therefore, decline in this part of the loss to the extent allowed amount is an important step in reducing of crop wastes. Combine header is a complex system which several factors are involved in its work. And, if these factors can be adjusted and controlled to suit the working conditions, to a large extent of crop loss can be prevented during the harvest. In this study, reel index, cutting height of crop and horizontal and vertical distance of reel from cutter bar were selected as the effective factors in header loss. In response surface method, central composite design was used to modeling and finding optimal levels of mentioned factors. The results showed that power model was the best model to describe the dependence of the independent variables and the dependent variable. The optimum conditions for minimum combine header loss (103 kg/ha) were obtained 1.2, 25 and 5 for reel index, cutting height of crop and horizontal and vertical distances of reel from cutter bar, respectively.