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Introduction: The number of adolescents with a severe chronic disease has increased in high-income countries due to improvements in the prognosis of childhood-onset chronic conditions. The transition from childhood to adulthood is a critical period that may be associated with increased mortality and morbidity. We aimed to estimate the prevalence of adolescents with a long-term disease (LTD) in France and assess their mortality and hospitalization risks relative to the general population. Materials and methods: We extracted a population-based cohort from the French national health insurance database that included 61,119 subjects who reached 14 years of age between 2005 and 2014. LTDs are diagnosed by patients’ physicians and then confirmed and registered by a physician of the national health insurance system. We assessed mortality and hospitalizations using data of patients who were between 14 and 21 years-old. Results: Among 14-year-old adolescents, 3.30% (95% confidence interval: 3.16–3.44) had a LTD. Their mortality rate between the ages of 14 and 21 years was 20.9/10,000 person-years (13.7–32.1) versus 1.9 (1.5–2.5) for adolescents without a LTD. Mortality was higher in males than females in youths without a LTD, but not in those with a LTD. We found a similar pattern for the risk of hospitalization for an external cause. The five-year probability of hospitalization was 61.8% among youths with a LTD versus 42.7% for those without. The rate of planned hospitalizations sharply fell at 19 years-of-age among youths with a LTD, whereas the rate of unplanned hospitalizations remained stable. Conclusion: The 3% of youths with a LTD have ten-fold higher mortality than those without and a high risk of hospitalization. The decrease in the rate of planned hospitalizations at age 19 among youths with a LTD may indicate differences in medical practice after transfer to adult care or a break in medical care. [ABSTRACT FROM AUTHOR]