Objective: The objectives of this study were to examine (1) the diagnostic accuracy requirements (from the cost-benefit point of view) of targeted ultrasonography versus genetic amniocentesis for prenatal detection of spina bifida in women with an elevated level of maternal serum ⍺-fetoprotein, (2) the ultrasonographic accuracy of previously published studies from the cost-benefit point of view, and (3) the possible economic impact for the United States of offering targeted ultrasonography instead of routine amniocentesis to this group of patients. Study Design: Our cost-benefit formula was based on the hypothesis that the cost of universal genetic amniocentesis in patients with an elevated concentration of maternal serum ⍺-fetoprotein in the second trimester should be at least equal to the cost of universal targeted ultrasonography, with amniocentesis used only for those with abnormalities on a sonogram. The main components of the formula included the diagnostic accuracy of targeted ultrasonography (sensitivity and specificity for detecting spina bifida), the cost of the amniocentesis package, the cost of targeted ultrasonography, and the lifetime cost of spina bifida not detected by targeted ultrasonography. After appropriate manipulation of the formula, a graph was constructed to represent the balance between the sensitivity and false-positive rate of targeted ultrasonography and was used to examine the accuracy of previously published ultrasonographic studies from the cost-benefit point of view. Sensitivity analyses included a range of prevalences of spina bifida in women with elevated maternal serum ⍺-fetoprotein from 1:50 to 1:200 and false-positive rates of targeted ultrasonography from 1% to 10%. Results: Assuming overall prevalences of spina bifida of 1:50, 1:100, or 1:200 among women with elevated maternal serum ⍺-fetoprotein, we found targeted ultrasonography to be beneficial only if the overall sensitivities for detecting fetal spina bifida were >88%, >76%, and >51%, respectively. All 17 studies published after the mid-1980s, which used the “cranial signs” for detecting spina bifida, had accuracies compatible with economic benefits (sensitivities, 92% to 100%; false-positive rates, 0% to 3%). Conclusion: The benefit of second-trimester targeted ultrasonography for fetal spina bifida depends on diagnostic accuracy (ie, sensitivity and false-positive rate). Currently achieved ultrasonographic accuracies are compatible with net benefits. Targeted ultrasonography in patients with an elevated level of second-trimester maternal serum ⍺-fetoprotein in the United States has the potential for annual savings of approximately $36 million to $49 million and for avoiding 268 fetal deaths. (Am J Obstet Gynecol 1999;180:1227-33.)