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Background: Congenital syphilis (CS) is a major and avoidable cause of neonatal death worldwide. In this study, we aimed to estimate excess all-cause mortality in children under 5 years with CS compared to those without CS. Methods and findings: In this population-based cohort study, we used linked, routinely collected data from Brazil from January 2011 to December 2017. Cox survival models were adjusted for maternal region of residence, maternal age, education, material status, self-declared race and newborn sex, and year of birth and stratified according to maternal treatment status, non-treponemal titers and presence of signs and symptoms at birth. Over 7 years, a total of 20 057 013 live-born children followed up (through linkage) to 5 years of age, 93 525 were registered with CS, and 2 476 died. The all-cause mortality rate in the CS group was 7·84/1 000 person-years compared with 2·92/1 000 person-years in children without CS, crude hazard ratio (HR) = 2·41 (95% CI 2·31 to 2·50). In the fully adjusted model, the highest under-five mortality risk was observed among children with CS from untreated mothers HR = 2·82 (95% CI 2·63 to 3·02), infants with non-treponemal titer higher than 1:64 HR = 8·87 (95% CI 7·70 to 10·22), and children with signs and symptoms at birth HR = 7·10 (95% CI 6·60 to 7·63). Among children registered with CS, CS was recorded as the underlying cause of death in 33% (495/1 496) of neonatal, 11% (85/770) of postneonatal, and 2·9% (6/210) of children 1 year of age. The main limitations of this study were the use of a secondary database without additional clinical information and the potential misclassification of exposure status. Conclusions: This study showed an increased mortality risk among children with CS that goes beyond the first year of life. It also reinforces the importance of maternal treatment that infant non-treponemal titers and the presence of signs and symptoms of CS at birth are strongly associated with subsequent mortality. Trial registration: Observational study. Enny S. Paixao and colleagues estimate excess all-cause mortality in children under five years with congenital syphilis compared to those without congenital syphilis in Brazil. Author summary: Why was this study done?: Despite global initiatives to eliminate mother-to-child transmission of syphilis and congenital syphilis, analyses of national data from several countries have shown an alarming rise in the number of congenital syphilis (CS) cases. The number of infants dying annually from congenital syphilis is unclear, but estimates suggest more than 661 000 CS cases would occur worldwide. There is a lack of studies estimating the excess all-cause mortality among live-born children with CS compared with live-born children without CS and with follow-up after the first year of life. What did the researchers do and find?: We analyzed a historical cohort of more than 20 million births in Brazil from 2011 to 2017. Live births with CS were 2 times more likely to die than their counterparts without CS, with the increased risk not totally explained by prematurity and low birth weight. The greatest mortality risks were observed in children with CS born to untreated mothers, with higher antibody titers, and with signs and symptoms of CS at birth. In live-born children registered with CS registry, CS and CS-related causes of death mainly drove the excess mortality, and specific external causes of death among older children with CS were more frequent than among those without CS. What do these findings mean?: The evidence highlights the importance of ensuring public health action for timely detection and maternal treatment to reduce vertical transmission and mitigate adverse pregnancy outcomes and CS-related child mortality. [ABSTRACT FROM AUTHOR]