Carpal tunnel syndrome (CTS) is among the most important of the family of musculoskeletal disorders caused by chronic peripheral nerve compression. Despite the large body of research in many disciplinary areas aimed at reducing CTS incidence and/or severity, means for objective characterization of the biomechanical insult directly responsible for the disorder have received little attention. In this research, anatomical image-based human carpal tunnel finite element (FE) models were constructed to enable study of median nerve mechanical insult. The formulation included large-deformation multi-body contact between the nerve, the nine digital flexor tendons, and the carpal tunnel boundary. These contact engagements were addressed simultaneously with nerve and tendon fluid-structural interaction (FSI) with the synovial fluid within the carpal tunnel. The effects of pertinent physical parameters on median nerve stress were explored. The results suggest that median nerve stresses due to direct structural contact are typically far higher than those from fluid pressure.