Short peripheral catheters (SPCs) are the most common intravenous devices used in medical practice. Short peripheral catheter thrombophlebitis (SPCT) is the most frequent complication associated with SPCs, causing discomfort and usually leading to removal of the catheter and insertion of a new one at a different site. The aim of this research was to explore whether biomechanical factors, in addition to biochemical factors, also play a role in the formation of thrombophlebitis. Hence, two of the biomechanical aspects of SPCT were investigated: the physical pressure load exerted by the SPC on the endothelial monolayer, and disturbances in the flow patterns due to the SPC. Endothelial activation was studied by subjecting human umbilical vein endothelial cells (HUVEC) to a weight load of SPC pieces and measuring the release profile of von-Willebrand Factor (vWF) over time, using ELISA. vWF release was chosen as the measure for endothelial activation since it was the major component of the Weibel-Palade Bodies (WPBs), which underwent exocytosis by endothelial cells during activation. Flow patterns were analyzed on a 3D computational fluid dynamics (CFD) model of a brachiocephalic vein with SPC. vWF release profiles were significantly higher in the HUVECs subjected to the load, indicating HUVEC activation. CFD simulations demonstrated a decrease in flow velocities along the catheter body, between the catheter and the vein, due to an enlarged boundary layer. Results indicate that the contact region between the SPC body and the vein wall can be partially responsible for SPCT development, and inflammatory and coagulatory processes initiated by stimulated endothelial cells may be amplified due to disturbed blood flow.