This paper presents an efficient high-order sharp-interface method for solving the three-dimensional (3D) Poisson equation with Dirichlet boundary conditions on a nonuniform Carte-sian grid with irregular domain boundaries. The new approach is based on the combina-tion of the fourth-order compact finite difference scheme and the preconditioned stabilized biconjugate-gradient (BiCGSTAB) method. Contrary to the original immersed interface method by LeVeque & Li , the new method does not require jump corrections, instead, the (regular) compact finite difference stencil is adjusted at the irregular grid points (in the vicinity of the interfaces of the immersed bodies) to obtain a solution that is sharp across the interface while keeping the fourth-order global accuracy. The contribution of the present work is the design of a fourth-order-accurate 3D Poisson solver whose accuracy and efficiency does not deteriorate in the presence of an immersed boundary. This is attributed to (i) the modification of the discrete operators near immersed boundaries does not lead to a wide grid stencil due to the compact nature of the discretization and (ii) a preconditioning technique whose efficiency and cost are independent of the complexity of the geometry and the presence or not of an immersed boundary. The accuracy and computational efficiency of the proposed algorithm is demonstrated and validated over a range of problems including smooth and ir-regular boundaries. The test cases show that the new method is fourth-order accurate in the maximum norm whether an immersed boundary is present or not, on uniform or nonuniform grids. Furthermore, the efficiency of the preconditioned BiCGSTAB is demonstrated with re-gard to convergence rate and “extra” floating-point operation (FLOPextra ) which is due to the presence of immersed boundaries. It is shown that the solution method is equally efficient for domains with and without irregular boundaries, with a negligible FLOPextra in the presence of immersed boundaries.