For the engineering design of large horizontal vessels with uneven multiple saddles, no clear specifications are given in design codes, especially with uneven settlements. In this paper, an analytical method based on three-moment theorem with settlements is introduced to evaluate the shear forces and bending moments at some critical cross-sections of a large horizontal pressure vessel supported on 10 saddles with uneven settlements. Zick's stress analysis method for a horizontal vessel supported on two saddles is extended to the multiple saddle arrangements. It is found that as a result of varied cross-section and uneven saddle supports, the shear forces and bending moments are different at different saddle sections. Finite element calculations are also performed to prove the analytical solutions. Results show that for the vessel without settlements, the bending moments and reactions obtained by the three-moment equation method are slightly larger than those obtained by finite element method. Non-uniform deformation of the vessel at different saddles may be contributed to the differences of the two results. For the vessel with settlements, the bending moments and reactions at some saddles obtained by the three-moment equation method are quite larger than those obtained by finite element method. But if the actual axis settlement of the vessel is applied to the three-moment equation method, the two results are close to each other. Experiments are also carried out to verify the reliability of the proposed method.