To evaluate the efficacy of high-dose leukocytapheresis (LCAP) using a large filter in patients with refractory rheumatoid arthritis (RA), we conducted a multicenter, nonrandomized, open-label clinical study. Thirty patients with highly active RA were treated with high-dose LCAP performed 3-5 sessions at 1-week intervals using a CS-180S filter (CS-180S group); the treatment involves the removal of leukocytes from a higher blood volume per body weight (100;Sml/kg). The clinical response was evaluated at 4 and 8 weeks after a series of LCAP using the 28-joint disease activity score (DAS28). Similar data of 53 patients treated with conventional LCAP (60;Sml/kg) using a standard filter, CS-100, were compared as a control (CS-100 group). The CS-180S filter demonstrated a higher adsorption capacity for leukocytes, particularly lymphocytes. The CS-180S group exhibited significant improvements in each item of DAS28 after treatment although the CS-100 group did not demonstrate such improvements in the CRP level and the ESR. Compared to the CS-100 group, the patients of the CS-180S group exhibited a tendency toward improvement with respect to the CRP level and ESR (P = 0.057 and 0.041, respectively). According to the EULAR improvement criteria based on DAS28, 60% and 45% of the patients from CS-180S and CS-100 groups achieved moderate or more responses, respectively, at 4 weeks after treatment. These results suggest that compared to conventional LCAP, high-dose LCAP may enhance the suppression of RA disease activity.