Background. Cystic fibrosis (CF) is an autosomal recessive disorder associated with an increased susceptibility to respiratory infections that cause progressive decline in lung function and lead to lung damage and chronic respiratory failure. To analyze the CF-related mortality trends in the Mexican population during a 22-year period.  We conducted a mortality trend analysis using death certificates data. Trends in CF-specific and in age-specific mortality rates were evaluated using Joinpoint regression analysis. Among subjects ≤40 years, 1184 CF-related deaths were identified. In 1999–2009 median age at death was 7 years compared to 10 years in 2010–2020. Overall mortality rate increased from 0.03 per 100,000 in 1999 to 0.06 per 100,000 in 2020. A decline in mortality rate for patients ≤28 days and an increase in mortality rate in older age groups was observed. Conclusion. The increasing trend in overall mortality, associated with a downward trend in neonatal mortality and an increase in median age at death is conceivably due to enhanced diagnosis, as well as major advances in treatment modalities, leading to higher survival rates. Key words: age at death, cystic fibrosis, epidemiology, low- and middle-income countries, mortality, survival rate.