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From 2012 to 2014, rates of congenital syphilis increased in Louisiana and Florida. We evaluated the effectiveness of early (first or second) and third trimester syphilis screening for the prevention of congenital syphilis in these high-morbidity states.Reported syphilis cases among pregnant women in Louisiana and Florida during January 1, 2013, to December 31, 2014, were reviewed for documented screening for syphilis in the first 2 trimesters and third trimester. Pregnant women with syphilis were linked to congenital syphilis records and stratified by whether the pregnancy led to a reported congenital syphilis case.Seven hundred ten pregnant women with syphilis in Louisiana and Florida were linked to 155 congenital syphilis cases. Three hundred seventy (52%) pregnant women with syphilis were staged as early syphilis (n = 270) or high-titer late or unknown duration-latent syphilis (n = 100), and 109 (70% of the total) were linked to congenital syphilis cases. Screening in the first 2 trimesters identified 513 pregnant women who tested positive for syphilis, and 470 (92%) potential congenital syphilis were averted. One hundred nine pregnant women tested positive for syphilis in the third trimester, and 85 (78%) had babies without congenital syphilis. During their pregnancy, 85 (12%) women tested negative at least once, and 55 (65%) had babies with congenital syphilis. Thirty-nine women had no reported syphilis screening 30 days or longer before delivery.Screening for syphilis both early and in the third trimester prevented many pregnant women with syphilis from having a baby with congenital syphilis. Preventing all congenital syphilis would likely require preventing all syphilis among women.