Reported cases of congenital syphilis have increased rapidly in recent years. The purpose of this study was to estimate first-year medical care expenditures among 1990 incident cases of infants diagnosed with congenital syphilis. The authors used a synthetic estimation model to calculate expenditures for congenital syphilis as the number of treated cases multiplied by cost per case. The number of cases was derived from surveillance data adjusted for underreporting and presumptive (false-positive) treatment. Cost per case was based on expected hospital and physician charges applied to case treatment protocols appropriate to case severity. Base-case estimated first-year medical expenditure for 1990 treated cases (N = 4,400) in 1990 was +12.5 million. In sensitivity analysis, estimates ranged from +6.2 million to +47 million. Substantial reduction in congenital syphilis treatment costs could be achieved through targeted public health interventions consisting of prenatal maternal screening and contact tracing of males testing positive for syphilis. Physicians should be aggressive in presumptive treatment of newborns, since this usually prevents future disability but represents a small portion of total national expenditure for congenital syphilis. More precise data on severe cases resulting in long-term disability are needed to make reliable cost estimates.