Abnormal peripheral perfusion (PP) worsens the prognosis of patients with septic shock. Polymyxin B-direct hemoperfusion (PMX-DHP) increases blood pressure and reduces vasopressor doses. However, the modification of PP following administration of PMX-DHP in patients with vasopressor-dependent septic shock have not yet been elucidated. A retrospective exploratory observational study was conducted in patients with septic shock treated with PMX-DHP. Pulse-amplitude index (PAI), vasoactive inotropic score (VIS), and cumulative fluid balance data were extracted at PMX-DHP initiation (T0) and after 24 (T24) and 48 (T48) h. Changes in these data were analyzed in all patients and two subgroups (abnormal PP PAI < 1 and normal PP PAI ≥ 1) based on the PAI at PMX-DHP initiation. Overall, 122 patients (abnormal PP group, n = 67; normal PP group, n = 55) were evaluated. Overall and in the abnormal PP group, PAI increased significantly at T24 and T48 compared with that at T0, with a significant decrease in VIS. Cumulative 24-h fluid balance after PMX-DHP initiation was significantly higher in the abnormal PP group. PMX-DHP may be an effective intervention to improve PP in patients with abnormal PP; however, caution should be exercised as fluid requirements may differ from that of patients with normal PP.