OBJECTIVE To evaluate the cost-effectiveness of routine antenatal varicella serologic screening of pregnant women with negative or indeterminate varicella histories. METHODS Routine antenatal varicella screening was evaluated using a decision analytic model. Outcomes were varicella cases, deaths, and life-years. Probabilities were derived from the literature, and sensitivity analysis was performed when data were imprecise or subject to variation. The analysis was repeated to include the effect of a policy of routine screening and vaccination of all adults. RESULTS Routine antenatal varicella screening of history-negative women was not cost-effective unless the cost of screening was decreased six-fold, varicella exposure rates were greater than 6%, or there was a greater than three-fold decrease in varicella exposure in women testing nonimmune compared with unscreened women. These results were not sensitive to alterations in varicella-zoster immunoglobulin (Ig) effectiveness, varicella communicability, rates and timing of contact reporting, costs (per case, pneumonia, and death), or serologic test performance. If performed as part of a policy of universal screening of all history-negative adults (with vaccination of the majority of those testing nonimmune), routine antenatal varicella testing became cost-effective. CONCLUSIONS Routine antenatal varicella screening of all pregnant women with negative or indeterminate varicella histories is not cost-effective. It could be cost-effective in groups of women with increased exposure risk, or if part of a policy of screening and vaccination of all adults.