PURPOSE: To evaluate the cost-effectiveness of a South Carolina program that tracks women with a pregnancy affected by a neural tube defect (NTD), counsels them, and provides folic acid supplements to reduce the risk of recurrence of an NTD in a subsequent pregnancy. METHODS: The resource costs of NTD recurrence prevention efforts in South Carolina were assessed. Program effectiveness was modeled on the basis of recurrence risk (2-5%) and the effectiveness of folic acid in prevention of recurrent NTDs (85-100%). The frequency of folic acid supplement use among women with a prior NTD-affected pregnancy in the United States is reported to range from 33% to 59%. In South Carolina, the majority of NTD-affected pregnancies are terminated and 31% end in a live birth with spina bifida. The estimated lifetime direct cost of spina bifida ($570,000 in 2003 dollars) incorporates new estimates of medical expenditures for adults with spina bifida and lost earnings of parental caregivers. Gains in Quality-Adjusted Life-Years (QALYs) were calculated three ways, using live births only, live births and stillbirths, and all pregnancy outcomes, respectively. RESULTS: The program is calculated to prevent 0.8 to 1.2 NTDs per year, at an annual cost of $158,000 in 2003 dollars, not including the costs of operating a state birth defects surveillance program. The cost-effectiveness (CE) ratio of NTD recurrence prevention in South Carolina is calculated to vary from $2,600 to $10,000 per QALY on the basis of South Carolina data on recurrence risk (4.8%), effectiveness of folic acid in recurrence prevention (100%), and use of folic acid supplements (85%), and a midpoint estimate from other U.S. states of folic acid supplement use without prevention program (46%). Substituting 3% and 87% as alternate values for the first two parameters, CE ratios are $10,000 to $40,000 per QALY. An influential but uncertain parameter is the frequency of folic acid supplement use among the target population in the absence of a recurrence prevention program, with associated CE ratios ranging from cost-saving to over $50,000 per QALY. CONCLUSIONS: The South Carolina NTD recurrence prevention program has cost-effectiveness ratios comparable with other health care interventions, but policy makers must decide on priorities for resource allocation. Also, research is needed to determine the cost-effectiveness of different strategies for NTD recurrence prevention.