Nanomechanical sensors and their arrays have been attracting significant attention for detecting, discriminating and identifying target analytes. The sensing responses can be partially explained by the physical properties of the receptor layers coated on the sensing elements. Analytical solutions of nanomechanical sensing are available for a simple cantilever model including the physical parameters of both a cantilever and a receptor layer. These analytical solutions generally rely on the simple structures, such that the sensing element and the receptor layer are fully attached at their boundary. However, an actual interface in a real system is not always fully attached because of inhomogeneous coatings with low affinity to the sensor surface or partial detachments caused by the exposure to some analytes, especially with high concentration. Here, we study the effects of such macroscopic interfacial structures, including partial attachments/detachments, for static nanomechanical sensing, focusing on a Membrane-type Surface stress Sensor (MSS), through finite element analysis (FEA). We simulate various macroscopic interfacial structures by changing the sizes, numbers and positions of the attachments as well as the elastic properties of receptor layers (e.g., Young’s modulus and Poisson’s ratio) and evaluate the effects on the sensitivity. It is found that specific interfacial structures lead to efficient sensing responses, providing a guideline for designing the coating films as well as optimizing the interfacial structures for higher sensitivity including surface modification of the substrate.