Objective: To determine the hospital cost of caring for newborn infants with congenital syphilis., Study Population: All live-born singleton neonates with birth weight greater than 500 gm at an inner-city municipal hospital in New York City in 1989., Methods: We compared the characteristics of 114 infants with case-compatible congenital syphilis with those of 2906 infants without syphilis. Cost estimates were based on New York State newborn diagnosis-related groups (DRG) reimbursements adjusted for length of stay, birth weight, preterm delivery, and selected maternal risk factors, including infection with the human immunodeficiency virus, cocaine use during pregnancy, and history of injected drug use., Results: For infants with congenital syphilis, the unadjusted mean cost ($11,031) and the median cost ($4961) were more than three times larger than those for infants without syphilis (p < 0.01). After adjustment, congenital syphilis was associated with an additional length of hospitalization of 7 1/2 days and an additional cost of $4690 (both p < 0.01) above mean study population values (7.13 days, $3473)., Conclusions: Based on the number of reported cases (1991 to 1994), the average annual national cost of treating infants with congenital syphilis is approximately $18.4 million (1995 dollars). This estimate provides a benchmark to assess the cost-effectiveness of strategies to prevent, diagnose, and treat the disease.