Introduction: Cystic fibrosis is the most common monogenic disease that can be life-threatening from childhood onward. In France, various measures have been implemented to address this condition, including the introduction of routine neonatal screening in 2002–2003 and the establishment of specialized care centers. This study examines the effects of this health policy by analyzing trends over time in age-specific mortality and the impact of demographic and clinical risk factors on mortality. Materials and Methods: The study population consists of patients from the French Cystic Fibrosis Registry. Mortality was analyzed cross-sectionally, using age-specific rates calculated over four periods: 1992–1996, 1997–2001, 2002–2006, and 2007–2011. The effect of risk factors for death was analyzed longitudinally using logistic regression on three cohorts of newborns enrolled in the Registry in 1992–1996, 1997–2001, and 2002–2006 and followed through 2012. Results: Mortality rates increase up to the age of 20–24 years but are, at each age, lower in recent periods than in earlier periods. The risk of death, all else being equal, is significantly higher among females and among severely malnourished patients, lower for the 1997–2001 and 2002–2006, and for patients aged 10–14 or 15 and older. Conclusion: Our results suggest that preventing malnutrition, multidisciplinary care provided by specialized treatment centers, and follow-up starting at birth could help reduce the mortality rate from cystic fibrosis in France.