Sickle cell trait (SCT) represents a significant global public health issue with approximately three million carriers in United States and over 300 million worldwide. Yet, the mortality risk of sickle cell trait is unknown. Early anecdotal research on SCT led to social bias and stigmatization of individuals with the trait, which unfortunately hindered the conduct of well-designed morbidity and mortality studies in this population. This resulted in SCT being perceived as a benign asymptomatic condition that protects against malaria and its importance confined to the genetic risk for sickle cell disease. As research in SCT gradually increased, it became evident that SCT is indeed a risk factor for several complications including exertional related rhabdomyolysis, chronic kidney disease, venous thromboembolism, and other morbidities. SCT red cells in abnormal physiologic conditions sickle and can cause morbidity and mortality. Additionally, SCT could potentially influence the severity of various illnesses. Individuals with SCT commonly experience hyposthenuria and are at risk for dehydration which could further exacerbate the severity of many medical problems. It is essential to determine if SCT is a risk factor for overall mortality. This study is the first population-level investigation of all-cause mortality risk for individuals with SCT. This longitudinal analysis included all live births with SCT identified by the California newborn screening (NBS) program between 1991 and 2013. For each newborn with SCT, three matched controls with hemoglobin AA were randomly selected from the NBS cohort. Controls were matched to SCT cases on year of birth, sex, race/ethnicity, and city of birth. SCT records with incomplete data for the matched variables or those with fewer than three matching controls were excluded from the analysis. SCT cases and controls were linked to all deaths within the state of California for the years 1991-2013 using statewide death data files. Cox proportional hazard ratios and 95% confidence intervals were calculated to compare mortality between individuals with SCT and controls with hemoglobin AA, including stratified by age (<1, 1-4, 5-14, 15-22). The study identified 94,240 live births with SCT (Table 1), which represents 96% of all SCT live births identified by the California NBS program in 1991-2013, and 282,720 matched controls. Between 1991 to 2013, there were 693 (0.74%) SCT deaths and 1,910 (0.68%) control deaths. Those with SCT had an increased mortality hazard rate compared to those with hemoglobin AA (11% higher, p=0.015). When stratified by age, mortality hazard rates in the age strata 1-4 years (44% higher, p= .0009) and 5-14 years (48% higher, p=.0047) were higher than those with hemoglobin AA (Table 2). These age strata describe periods of follow up time, and an individual may appear in more than one stratum. Mortality hazard ratios calculated for each age stratum are conditional to individuals surviving to the starting age of that stratum. This analysis of mortality risk for a cohort of over 94,000 infants identified with SCT is the first of its kind and adds important information to the assessment of health risk for the condition. This is the first study that reports a higher risk of mortality for children and young adults with SCT compared to those with hemoglobin AA. These findings highlight the need for comprehensive research, including confirming the study results in other longitudinal sickle cell trait population-level studies and investigation into underlying causes of death, to inform clinical management and counseling for individuals with SCT.