Background: The long-term natural history of microscopic colitis remains uncertain. Aim: To describe the mortality in a large unselected cohort of patients with microscopic colitis. Methods: All Danish patients above 18 years with an incident diagnosis of microscopic colitis from 2001 to 2018 were identified from nationwide registries and compared to age- and sex-matched controls (variable 1:10 ratio). Patients were categorised according to subtypes: lymphocytic colitis and collagenous colitis. The relative risk of death by any cause was analysed with Cox regression models estimating both crude and comorbidity-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Cause-specific death was evaluated with cumulative incidence functions. An E-value was calculated to address the impact of unmeasured confounding. Results: The final cohort consisted of 14 024 patients with microscopic colitis. The mean follow-up was 5.8 (standard deviation SD, 2.9) years and the mean age at diagnosis was 61.1 (SD 13.9) years, 70% were women and 41% were diagnosed with lymphocytic colitis. The main results showed a 25% increased risk of all-cause death in patients with microscopic colitis; however, the relative risk was attenuated to 9% when adjusting for comorbidities (95% CI, 1.05-1.14). The E-value indicates that unmeasured confounding could explain the residual observed increased all-cause mortality. Mortality was significantly increased in patients with both lymphocytic colitis (HR 1.15; 95% CI, 1.08-1.23) and collagenous colitis (HR 1.06; 95% CI, 1.01-1.12) in fully adjusted analyses. The absolute difference in death between patients with microscopic colitis and matches was 0.9% at 1 year, 2.8% at 5 years, 5.0% at 10 years and 3.0% at 15 years. Cumulative incidence functions showed that patients with microscopic colitis were more likely to die due to smoking-related diseases including ischemic heart and lung diseases, but had a significant decreased risk of death due to colorectal cancers (P < 0.0001). Conclusion: In an unselected large nationwide cohort of patients with microscopic colitis, the risk of death was significantly increased compared to the background population. However, the increased mortality seemed to be associated to a high burden of comorbidities and unmeasured life-style factors including smoking and not microscopic colitis per se.