Objectives: Severe consequences of mother-to-child transmission of syphilis and high increasing incidence of congenital syphilis remains an important public health problem in Brazil. Our objective was to assess the cost-effectiveness of a rapid point-of-care test (RT) and treatment of positive mothers immediately compared with a laboratory-based standard test (ST) with treatment at next follow-up visit. Methods: A decision analytic model was developed to estimate the incremental cost-effectiveness ratio (ICER) between antenatal syphilis screening strategies. The model was built with lifetime horizon from Brazilian health system perspective using 3% and 5% discount rates. A hypothetical cohort of pregnant women at reproductive age were used in the model. Health outcomes: low birth weight, stillbirths, neonatal deaths and congenital syphilis were estimated in disability-adjusted life-years (DALYs) lost. Microcosting study and secondary data provided parameters of direct medical costs. Probabilistic sensitivity analysis was undertaken. Results: For base case, the mean cost per pregnant woman screened was $2.63 (RT) and $2.48 (ST), respectively. Maternal syphilis was associated with a loss of 0.0043 DALYs (RT) and 0.0048 DALYs (ST) per mother screened. Expected value of incremental cost per DALY averted was $298.08. After 10 000 probabilistic sensitivity analysis model runs, incremental cost and health benefits were $0.15 (95% credible interval –1.56 to 1.92) and 0.00042 DALYs (95% credible interval –0.0036 to 0.0044), respectively, with a mean ICER of $357.44 per DALY. Screening with RT has a 58% chance of being the optimal strategy at a threshold of $3,200 per DALY. Conclusions: In Brazil, antenatal screening with syphilis RT and immediate treatment is likely to be cost-effective compared with standard screening and must be prioritized in local settings.