Purpose To determine the efficacy and safety of trajectory infiltration with 1:150 000 Norepinephrine (NE) in reducing blood loss during percutaneous nephrolithotomy (PCNL). Materials and methods This is a prospective randomized double-blinded placebo-controlled trial. In all, 140 consecutive patients underwent PCNL for the management of large renal calculi. They were randomly assigned (1:1) to one of either study groups, the NE-PCNL group (70 patients whose PCNL-trajectory was infiltrated by NE) or the Placebo group (saline PCNL) (70 patients whose PCNL tracts were infiltrated by normal saline). Procedure-related blood loss (the primary outcome) was assessed and statistically analyzed. Also, all other procedure-related events and complications were recorded and compared. Results The median blood loss was 378 ml (IQR: 252–504) in the NE-PCNL group versus 592 ml (IQR: 378–756) in the S-PCNL group (p