Background: Peripherally inserted central catheters (PICCs) are now widely used in modern medicine, and associated complications have also increased. Central line associated bloodstream infection (CLABSI) is the most serious complication because it can cause longer hospital stays and increase costs. Furthermore, it can contribute to dire consequences for critically ill patients. Subcutaneous tunnelling for central venous catheters is an accepted method to reduce the risk of CLABSI. However, it is not generally adopted for PICC placement in most hospitals because its safety and efficacy have not been fully evaluated. Methods: In this multi-institutional, prospective, non-blinded pragmatic randomized controlled trial, 1694 patients treated at five referral hospitals were assigned to one of two parallel arms (conventional and tunnelled PICC groups) using computer-generated stratified randomization. The conventional group underwent PICC placement by the usual practice. In the tunnelled PICC (tPICC) group, additional subcutaneous tunnelling was applied. Patients will be followed until PICC removal or the end of this study. The primary endpoint was whether subcutaneous tunnelling reduced the rate of CLABSI compared to the conventional method. The secondary endpoints are comparison of technical success rates, complications including exit-site bleeding or infection, and procedure time difference between the groups.Discussion: Subcutaneous tunnelling is a widely used method to reduce catheter-associated infection. However, it has not been thoroughly applied for PICC. A randomized trial is needed to more objectively assess the effects of subcutaneous tunnel in PICC placement. This TUNNEL-PICC trial will provide evidence for the effectiveness of subcutaneous tunnelling to decrease the risk of CLABSI.Trial registration: Clinical Research Information Service (CRiS) KCT0005521