Purpose: In observational trials, midodrine decreased vasopressor duration, length of stay (LOS), and mortality but not in randomized controlled trials. The goal of this study is to assess the efficacy and safety of using midodrine to wean intravenous (IV) vasopressors in patients with septic shock. Materials and Methods: This single-center, retrospective study was conducted at a 505-bed community teaching hospital between September 2021 and December 2022. Patients were ≥18 years of age with septic shock, admitted to the intensive care unit (ICU), required IV vasopressors for hemodynamic support, and demonstrated clinical stability. Outcomes were compared across patients receiving IV vasopressors with midodrine vs. IV vasopressors alone. Results: Among 139 patients, midodrine was associated with increased time to IV vasopressor discontinuation, 5.5 ± 6.5 days vs. 2.4 ± 1.6 days (mean difference 3.1, 95% confidence interval 1.5 to 4.7, P = 0.0003). In patients started on midodrine within 48 hours of stability, time to IV vasopressor discontinuation was similar to the vasopressor alone cohort. Secondary outcomes including ICU and hospital LOS after vasopressor initiation, ICU and in-hospital mortality, and ICU readmission were similar between groups. Twenty patients were discharged from the hospital on midodrine. Incident bradycardia was increased in the midodrine group, but hypertension was similar between groups. Conclusions: Patients in the midodrine group exhibited a longer time to vasopressor discontinuation; however, this difference was only apparent in those with midodrine initiation more than 48 hours after hemodynamic stability in a post-hoc subgroup analysis. These outcomes may be attributed to midodrine being used as salvage therapy.