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Despite early diagnosis through neonatal screening and improved access to vaccines, antibiotics, and disease-modifying therapies, many individuals with sickle cell disease (SCD) die before age 60. This study evaluated causes and independent predictors of mortality in a Brazilian SCD population using data from the multicenter REDS-III cohort [2013–2018], which included six centers. Eligible patients were randomly enrolled during routine visits. Clinical and laboratory data were abstracted from medical records, and deaths were confirmed via chart review and linkage to the national death certificate database. Key variables were compared between deceased and surviving adults using Chi-square and Mann-Whitney tests. A multivariable Cox regression model identified independent predictors of mortality. Children were excluded from regression analysis due to low pediatric mortality. Among 2,793 participants, 1,558 (55.8%) were under 18. By the end of follow-up, 159 (5.7%) had died—142 adults and 17 children. Median life expectancy was 65.7 years. Infection was the leading cause of death (33.3%), followed by non-infectious pulmonary conditions (25.2%) and neurologic disease (14.5%). Cause of death was unknown in 3.1% of cases. In adults, independent predictors of mortality were older age [HR 1.03; 95% CI 1.01–1.04], iron overload [HR 1.68; 95% CI 1.09–2.60], and prior hospital admissions [HR 1.68; 95% CI 1.10–2.56]. The mortality burden in SCD is shifting toward adults, particularly in the third and fourth decades of life. Individuals with SCD in Brazil die about 10 years earlier than the general population. The main causes of death in our cohort were infections, acute chest syndrome and stroke, highlighting the need for prompt recognition and treatment of these complications. Screening and treatment for iron overload and closer monitoring and consideration of disease modifying therapies for patients with frequent hospital admissions are important as both were identified as independent predictors of mortality.