OBJECTIVE: Despite the biological drugs, the treatment of moderate to severe ulcerative colitis is still a challenge, particularly in resource-limited settings. The aim of this study was to assess the efficiency of biological drugs and tofacitinib for moderate to severe ulcerative colitis in the Spanish context. METHODS: A Markov model was built to simulate the progression of moderate to severe ulcerative colitis in a cohort of patients. The model used a time horizon of 10 years. The perspective chosen was the National Health Service, with a discount rate of 3%, and a threshold of euro30,000/quality adjusted life-year (QALY). It carried out a one-way sensitivity analysis and probabilistic sensitivity analysis. RESULTS: The comparison of infliximab with adalimumab and golimumab estimated an incremental cost-effectiveness ratio (ICER) of euro43,928.07/QALY and euro31,340.69/QALY, with a difference of - 0.43 and - 0.82 QALY, respectively. Vedolizumab vs infliximab achieved an ICER of euro122,890.19/QALY with a gain of 0.46 QALY. The comparison of infliximab with tofacitinib yielded an estimated ICER of euro270,503.19/QALY, with a slight gain in QALY (0.16). The one-way sensitivity analysis showed a robust study. CONCLUSION: For a threshold of euro30,000/QALY, adalimumab was the most cost-effective treatment versus infliximab for moderate to severe ulcerative colitis in Spain.