PURPOSE: Septic shock refractory to high-dose vasopressors confers unacceptably high mortality, however, the impact of timing of peak vasopressor dose exposure on outcomes is unknown. METHODS: This retrospective cohort study included adults who required a vasopressor dose ≥0.5 μg/kg/min norepinephrine-equivalents in the first 24 h of septic shock. We used the median time to peak vasopressor dose to stratify patients into 'early' and 'late' groups. Multivariable Cox proportional hazards regression was used to assess the impact of time to peak vasopressor exposure on mortality. RESULTS: The median time to peak vasopressor dose exposure was 6 (3,13) hours, defining the early (n = 351) and late (n = 351) groups. In the severity-adjusted multivariable analysis, the early group was less likely to die within 28 days (HR 0.76, 95 % CI 0.58-0.99). The early group experienced significantly more days alive and free from renal replacement therapy, vasopressors, mechanical ventilation, and quicker independence from vasopressors (HR 1.40, 95 % CI 1.17-1.69). Mesenteric ischemia and arrhythmias were more frequent in the late group. CONCLUSIONS: In vasopressor-refractory septic shock, achieving the peak vasopressor dose within the first six hours of shock onset was associated with reduced mortality and more days alive and free from organ-support therapies.