Phenylephrine (PE) and norepinephrine (NE) may be used to maintain adequate blood pressure and tissue perfusion in patients with septic shock, but the effect of NE combined with PE (NE-PE) on mortality remains unclear. We hypothesized that NE-PE would not inferior to NE alone for all-cause hospital mortality in patients with septic shock.This single-center, retrospective cohort study included adult patients with septic shock. According to the infusion type, patients were divided into the NE-PE or NE group. Multivariate logistic regression, propensity score matching and doubly robust estimation were used to analyze the differences between groups. The primary outcome was the all-cause hospital mortality rate after NE-PE or NE infusion.Among 1, 747 included patients, 1, 055 received NE and 692 received NE-PE. For the primary outcome, the hospital mortality rate was higher in patients who received NE-PE than in those who received NE (49.7% vs. 34.5%, p < 0.001), and NE-PE was independently associated with higher hospital mortality (odds ratio = 1.76, 95% confidence interval = 1.36-2.28, p < 0.001). Regarding secondary outcomes, patients in the NE-PE group had longer lengths of stay in ICU and hospitals. Patients in the NE-PE group also received mechanical ventilation for longer durations.NE combined with PE was inferior to NE alone in patients with septic shock, and it was associated with a higher hospital mortality rate.© 2023. The Author(s).