The purpose of this study was to investigate the pathological influence of mechanical stresses that occur inside the carpal tunnel during exertions of the hand. Microscopic changes in fibrous tissue density, in synovial, subsynovial, and adjacent connective tissue density, and in median nerve epineurium density, arteriole wall muscle thickness, and arterial and venule endoproliferation were investigated at 5-mm increments along a 9-cm range of six postmortem wrist specimens. All of these changes increased from normal in the proximal portions of the wrist, -30 to -40 mm from the wrist crease, to maximal values 0- to 20-mm distal to the wrist crease. The changes then decreased toward normal in the distal sections, 20 to 40 mm. The location and character of these changes suggest that repeated exertions with a flexed or extended wrist are an important factor in their etiology. The consistency with which they are found in this and other studies suggests that extreme changes associated with highly repetitive work or additional stress factors are required to produce symptoms in most cases of carpal tunnel syndrome.