We aimed to evaluate whether subcutaneous tunneling in peripherally inserted central catheters (PICC) placement could reduce the occurrence of central-line associated blood stream infection (CLABSI). We conducted an open-label, multicentre, randomized, controlled trial in five tertiary hospitals. Adult hospitalized patients requiring a PICC were randomized in a one-to-one ratio to conventional (cPICC) or tunneled PICC (tPICC) arms using a centralized web-based computer-generated stratified randomization. CLABSI rates between groups were compared in a modified intention-to-treat population. Safety including the incidence of exit-site infection or hemorrhage-associated catheter removal were also compared. This trial was registered with Clinical Research Information Service of Republic of Korea (KCT0005521). From November 2020 to March 2023, 1,324 participants were enrolled and randomly assigned to tPICC (n=662) and cPICC (n=662). This study was terminated early due to the cohort CLABSI rate being lower than estimated, therefore, the original sample size of 1,694 would render the study underpowered to detect a difference in CLABSI rates. In the tPICC, CLABSI occurred in 13 of 651 participants over 11,071 catheter-days (1.2/1,000 catheter-days), compared with 20 among 650 patients with cPICC over 11,141 catheter-days (1.8/1,000 catheter-days, rate ratio 0.65, 95% CI 0.30-1.38, p=0.30). The incidence of exit-site infection (29 tPICC, 36 cPICC, p=0.5) and hemorrhage-associated catheter removal (11 tPICC, 11 cPICC, p=0.99) was not different between both groups. Due to insufficient sample size, this study could not demonstrate a statistically significant CLABSI risk reduction in the tPICC group compared to the cPICC group. Both groups had similar rates of exit site infection and bleeding.