Abstract: The reduction of the volume and airflow pressure drop in the inertia separation chamber of 4ZTL-1800 combine harvester threshing prior to cutting is a constant target. In order to optimize its structure, the effects of structural parameters of the inertia separation chamber and airflow velocities on pressure drop were investigated by the method of quadratic orthogonal rotation combination design test with four factors and five levels. The three structural factors are separation board length, chamber height and chamber length. The effect law of the three factors on pressure loss was obtained. Under the condition of ensuring the separation efficiency with the objective of minimal pressure loss, the optimized structural parameters were obtained as follows: separation board length 1180 mm, chamber height 1120 mm, separation chamber length 1700 mm. These analyses are useful for the design of the inertia separation chamber.