To accurately simulate wave-structure interaction based on fully nonlinear potential flow theory, a three-dimensional (3 D) high-order immersed-boundary adaptive harmonic polynomial cell (IB-AHPC) method is proposed. Both the free surface and body surface are immersed in background octree cells that are adaptively refined near the boundaries of interest, thereby dramatically reducing computational costs without loss of accuracy. We also propose an easy-to-implement IB strategy to deal with possible instabilities in the time-domain solution arising from the intersection of Dirichlet–Neumann boundaries. For a linearized problem of wave-wall interaction, a matrix-based stability analysis is performed, providing mathematical support for the robustness of the proposed IB strategy. In contrast to the two-dimensional HPC method, compressed cells are found to offer superior stability compared to stretched cells in the vertical direction, while equal mesh aspect ratio in the horizontal plane is superior. Cubic octree cells are, however, still preferred in practice. The free surface is primarily described by a set of massless background wave markers; however, to address the challenges of IB methods in tracking the free surface evolution near the structure, additional body-fitted wave markers are introduced close to the waterline. The information exchange between these two sets of wave markers is realized by radial basis function (RBF) interpolation. While standard RBF schemes have grid-size-dependent filtering performance, we propose a normalized RBF scheme, which is then optimized in terms of the number of neighboring nodes, a smoothing coefficient and the basis functions. Excellent accuracy properties of the proposed 3 D IB-AHPC method are demonstrated by studying fully nonlinear wave propagation. The method is further applied to study relevant fully nonlinear wave-structure interaction problems, including sloshing in 3 D rectangular tanks and wave diffraction of a bottom-mounted cylinder in regular waves. Satisfactory agreement is demonstrated with existing experimental and numerical results, suggesting that the proposed 3 D IB-AHPC method is a promising potential-flow method in marine hydrodynamics.