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Background: Congenital syphilis is an important public health problem in low- and middle-income countries. Poor neonatal health outcomes associated with the disease may lead to maternal psychological distress and feelings of helplessness. This study aimed to evaluate the quality of life, anxiety levels, depressive symptoms, and sexual function in mothers of neonates with congenital syphilis in the Northeast of Brazil., Methods: This cohort study compared patient-centered outcomes between mothers of neonates with congenital syphilis and mothers of healthy neonates during the first three months of the postpartum period. The study was conducted in Sergipe state, Northeast Brazil, a region with one of the highest rates of congenital syphilis (14·1 cases per 1000 live births). Quality of life, depressive symptoms, anxiety levels, and sexual function were evaluated by using the World Health Organization Quality of Live - shortened version (WHOQoL-BREF) instrument, Beck Depression Inventory, Spielberger State-Trait Anxiety Inventory, and Female Sexual Function Index, respectively. Unadjusted differences between groups were anayzed by using the Mann-Whitney test. Glass's delta with 95% confidence interval (CI) was used to measure the effect size., Findings: Sixty-three women were included in each group. During the in-hospital stay, mothers of neonates with congenital syphilis had lower scores for overall quality of life ( p  < 0·001; large effect size: -0·559 [95% CI -0·683 to -0·405]) and higher levels of anxiety ( p  < 0·001; large effect size: 0·558 [95% CI 0·403 to 0·681]) and depressive symptoms ( p  < 0·001; large effect size: 0·561 [95% CI 0·407 to 0·684]) than mothers of healthy neonates. Three months after childbirth, we found persistent depressive symptoms ( p  = 0·021; small effect size: 0·239 [95% CI 0·041 to 0·419]) and low overall sexual function ( p  = 0·041; small effect size: -0·211 [95% CI -0·394 to -0·012]) among mothers of neonates with congenital syphilis compared to the control group., Interpretation: Mothers of neonates with congenital syphilis present poorer quality of life, mental health, and sexual function compared to mothers of healthy neonates., Funding: Brazilian Federal Agency for Coordination of Improvement of Higher Education Personnel (CAPES)., Competing Interests: The authors declare that there is no conflict of interest. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001., (© 2021 The Authors.)