Background & Aims: Reports of multiple sclerosis (MS), demyelination, and optic neuritis (ON) associated with anti-tumor necrosis factor α therapy resulted in warnings on prescribing instructions for infliximab, etanercept, and adalimumab. However, the underlying relationship between IBD and these neurologic conditions has not been established. Methods: We performed a retrospective cohort study and a retrospective cross-sectional study using 1988 to 1997 data from the General Practice Research Database. A total of 7988 Crohn’ s disease and 12,185 ulcerative colitis patients were matched for age, sex, and primary care practice to 80,666 randomly selected controls. In the cohort study, incident cases of MS, demyelination, and/or ON (MS/D/ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD. In the cross-sectional study, the diagnosis of MS/D/ON could either precede or follow the IBD diagnosis. Results: In the cohort study, the incidence of MS/D/ON was higher in patients with Crohn’ s disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis (ulcerative colitis incidence rate ratio [IRR], 2.63; 95% confidence interval, 1.29-5.15;Crohn’ s disease IRR, 2.12; 95% confidence interval, .94-4.50). In the cross-sectional study, MS/D/ON was more prevalent in patients with Crohn’ s disease and ulcerative colitis compared with their matched controls (Crohn’ s disease odds ratio, 1.54; 95% confidence interval, 1.03-2.32; ulcerative colitis odds ratio,1.75; 95% confidence interval, 1.28-2.39). Conclusions: Demyelinating diseases occur more commonly among patients with IBD than among non-IBD patients. Future studies should clarify whether treatment with tumor necrosis factor α blockers results in further increased incidence of MS/D/ON among IBD patients. Background & Aims: Reports of multiple sclerosis (MS), demyelination, and optic neuritis (ON) associated with anti-tumor necrosis factor α therapy resulted in warnings on prescribing instructions for infliximab, etanercept, and adalimumab. However, the underlying relationship between IBD and these neurologic conditions have not been established. Methods: We performed a retrospective cohort study and a retrospective cross-sectional study using 1988 to 1997 data from the General Practice Research Database. A total of 7988 Crohn’s disease and 12,185 ulcerative colitis patients were matched the age, sex, and primary care practice to 80,666 randomly selected controls. In the cohort study, incident cases of MS, demyelination, and / or ON (MS / D / ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD. In the cross-sectional study, the diagnosis of MS / D / ON could either precede or follow the IBD diagnosis. Results: In the cohort study, the incidence of MS / D / ON was higher in patients with Crohn’s disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis incidence (IRR), 2.63; 95% confidence interval, 1.29-5.15 ; Crohn’s disease IRR, 2.12; 95% confidence interval, .94-4.50). In the cross-sectional study, MS / D / ON was more prevalent in patients with Crohn’s disease and ulcerative colitis compared with their matched controls (Crohn’s disease odds ratio, 1.54; 95% confidence interval, 1.03-2.32; ulcerative colitis odds ratio, 1.75; 95% confidence interval, 1.28-2.39). Conclusions: Demyelinating diseases occur more among patients with IBD than intra- -IBD patients. Future studies should clarify whether treatment with tumor necrosis factor α blockers results in further increased incidence of MS / D / ON among IBD patients.