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Ulcerative colitis (UC) is associated with significant health care utilization and costs. We assessed UC direct medical costs in Quebec, Canada, in 2 time periods (1998–2004 and 2005–2011) and determined changes over time.Because the introduction of anti–tumor necrosis factor α may have influenced the UC cost, we used the Quebec health services administrative databases and the same inclusion criteria to create 2 separate UC cohorts, before (1998–2004) and after (2005–2011) anti–tumor necrosis factor α introduction.The postcohort included 801 patients and the precohort 716 patients. Overall, cohorts were predominately women and were comparable in terms of patient's demographics and comorbidities. Corticosteroid use, emergency department visits and hospitalizations for colectomies, and other gastrointestinal disorders were fewer in the postcohort versus precohort. The median daily cost (interquartile range) was $16.96 ($6.80–$48.16) for the postcohort and $18.65 ($7.82–$53.31) for the precohort. In generalized linear models with log link and gamma distribution, the adjusted daily cost ratios (95% confidence interval) in the postcohort versus precohort was 0.75 (0.67–0.85). Older age at inclusion, low income, lower socioeconomic status, and previous use of gastroprotective agents, antidepressants, and sulfasalazine, methotrexate, or cyclosporine were associated with increased costs. Women and those who visited a gastroenterologist in the previous year incurred lower costs.The mean UC daily cost decreased from 2005 to 2011 as compared to 1998 to 2004 because of a decrease in rates of colectomy and other gastrointestinal hospitalizations and emergency department visits. Further investigation is required to determine the reasons for these changes.