AIM: To compare the effects and efficacy of methoxyamine and norepinephrine on sublingual microcirculation in patients with high-altitude septic shock. METHODS: A total of forty-six patients with septic shock from the Xining area of Qinghai Province were randomized into two groups: the M-hydroxylamine group (Group M, n=22) and the norepinephrine group (Group N, n=24). Baseline data as well as the incidence of acute kidney injury (AKI), distal limb necrosis/ischemia, and 28-day survival rates were documented. Sublingual microcirculation parameters were monitored and recorded at four time points: before treatment (T0), 24 hours post-treatment (T1), 48 hours post-treatment (T2), and 72 hours post-treatment (T3) using side-flow dark-field (SDF) imaging. The parameters included total vascular density (TVD), perfused vascular density (PVD), perfused vessel ratio (PPV), microvascular flow index (MFI), and heterogeneity index (HI). Additionally, changes in heart rate (HR), mean arterial pressure (MAP), blood urea nitrogen (BUN), serum creatinine (Cr), and lactate (Lac) levels were also recorded. RESULTS: There were no significant differences between the two groups in terms of baseline data, incidence of AKI, distal limb necrosis/ischemia, and 28-day survival rate. Additionally, there were no significant differences in HR, MAP, and Lac indices between the two groups at any time point. However, within-group comparisons showed that HR, MAP, and Lac indices improved over the course of treatment, with statistically significant differences. The BUN level at the T3 time point was significantly lower in the mehydroxyamine group compared to the norepinephrine group (P<0.05). Similarly, Cr levels were significantly lower at both T2 and T3 time points (P<0.05). There were no significant differences in sublingual microcirculation indices between the two groups at any time point. However, TVD, PVD, PPV, MIF, and HI in both groups improved over the course of treatment, with statistically significant differences. CONCLUSION: Both methoxyamine and norepinephrine can enhance both the macrocirculation and sublingual microcirculation in patients with septic shock at high altitudes. Additionally, methoxyamine leads to a faster recovery of creatinine levels within 72 hours.