Background: This prospective study assessed the impact of selective leukocytapheresis (SLA) on mucosal inflammation in patients with active ulcerative colitis (UC) by endoscopic investigations and measurement of mucosal cytokine profiles. Materials and Methods: Twenty-eight patients with moderately active UC received 5 SLA sessions with the Adacolumn over 5 consecutive weeks. The Adacolumn leukocytapheresis carriers selectively adsorb granulocytes, monocytes/macrophages, and smaller subsets of lymphocytes (FcγR and complement receptors bearing leukocytes). Before and after treatment, mucosal biopsies were obtained from multiple sites in the large bowel. As control, colonic biopsies from 20 patients without bowel inflammation were examined. Mucosal cytokines were measured by enzyme-linked immunosorbent assay. Results: At entry, the mucosal concentrations of interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were significantly higher compared with the control group, whereas IL-1ra/IL-1β ratio was significantly lower. Clinical remission was achieved in 19 (68%) patients. In patients with clinical remission but not in those without remission, the mucosal tissue concentrations of IL-1β, IL-1ra, IL-6, IL-8, and TNF-α significantly decreased, whereas the IL-1ra/IL-1β ratio significantly increased. Furthermore, endoscopic remission of mucosal inflammation was observed in 14 (50%) patients, which was associated with a decline in mucosal IL-1β, IL-1ra, IL-6, IL-8, and TNF-α and an increase in IL-1ra/IL-1β ratio. Conclusions: Depleting granulocytes and monocytes/macrophages by SLA should mitigate cytokine profiles in the intestinal mucosa and correct an imbalance between pro- and anti-inflammatory cytokines in active UC.