Purpose: Methylene blue (MB) has been used to increase blood pressure in patients with septic shock by acting on guanylate cyclase and nitric oxide synthase (NOS). Objective: To determine whether the administration of MB to patients in the initial phase of septic shock leads to a reduction in the use of vasopressors compared to that in the control group. Methods: This was a 1:1 randomized clinical trial of two groups (methylene blue and control). We used MB after uid replacement, vasopressors and antibiotic therapy. Patients received a loading dose of MB (3 mg/kg) and maintenance (0.5 mg/kg/h) for 48 hours. Vasopressor doses, laboratory test results, inammatory and anti-inammatory cytokine levels, and hemodynamic monitoring were recorded before the infusion of MB (T1) and after 20 minutes (T2), 2 hours (T3), 24 hours (T4), 48 hours after the infusion started (T5) and 24 hours after weaning (T6). Results: Methylene blue therapy started within 72 hours of septic shock. The methylene blue group showed na immediate reduction in NOR dosage, earlier reduction in VAS dosage, and higher IL-10 levels compared to the control group. Integrative network analysis highlighted NO and IL-10's roles in coordinating correlations with "Hemodynamic Monitoring" in the control and methylene blue groups, respectively. Conclusion: Early methylene blue (MB) administration alongside standard septic shock treatment reduces vasopressor doses, possibly involving nitric oxide (NO) mechanisms. A possible mechanism of action may involve modulation of inammatory and anti-inammatory mediators, enhancing immune response. However, larger and longer studies are needed for validation.