OBJECTIVE Diabetes is increasingly common in cystic fibrosis, but little information describing its influence on mortality exists. Using national U.K. data, in this study we document diabetes-specific mortality rates, estimate the impact of diabetes on survival, and estimate population-attributable fractions. RESEARCH DESIGN AND METHODS This retrospective cohort study identified 8,029 individuals aged 0–65 years from the U.K. Cystic Fibrosis Registry (1996–2005). A total of 5,892 patients were included in analyses of mortality rates, and 4,234 were included in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling. RESULTS During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8 per 100 person-years (95% CI 1.6–2.0). The age-adjusted mortality rates per 100 person-years were 2.0 (1.8–2.4) in female subjects and 1.6 (1.4–1.9) in male subjects, and 4.2 (3.4–5.1) in individuals with diabetes vs. 1.5 (1.3–1.7) in those without diabetes. Independent risk factors for death included diabetes (hazard ratio 1.31 [95% CI 1.03–1.67], female sex (1.71 [1.36–2.14]) plus poorer pulmonary function, lower BMI, Burkholderia cepacia infection, absence of Staphylococcus aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use. CONCLUSIONS Individuals with cystic fibrosis die earlier if they have diabetes, which, if delayed or better treated, might reasonably extend survival; this hypothesis merits testing.