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 < 0.0001). In addition, Hemoglobin and Hematocrit deficits were lower in NE-PCNL (p < 0.05). Patients who were randomized to the NE-PCNL group had a higher immediate stone-free rate (SFR) (80%) compared with those of the S-PCNL group (70%) (p = 0.034). However, no statistical differences were found in the final SFR. The reported overall complications between the 2 groups were similar (p > 0.05). Indeed, bleeding-related complications were 1 (1.4%) versus 10 (14.3%) for NE-PCNL and S-PCNL, respectively (p = 0.009). Conclusions: Trajectory infiltration of PCNL tracts by NE was found to be effective and safe in mitigation of PCNL-related blood loss. This step is a timeless and cost-effective as NE is readily available in surgical theaters and of very low cost.