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The aim of this study was to determine whether incorporation of dried blood alpha fetoprotein (AFP) into first trimester screening using the biochemical markers free Beta human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) can improve screening performance.A retrospective study of 34 Down syndrome and 1185 unaffected dried blood specimens. First trimester dried blood AFP was performed using in-house immunofluorometric time-resolved assay. False positive and detection rates were determined from modeling.The multiple of the median in Down syndrome cases was 0.73. At a fixed 5% false positive rate, incorporating AFP into a free Beta hCG, PAPP-A, and nuchal translucency protocol adds 2% detection resulting in detection rates of 92% to 94% depending on the gestational age of the blood draw. At a fixed 90% detection rate, AFP reduced the false positive rate by 1.0 to 1.6 percentage points depending on gestational age. Using a cutoff of 1/1000, the combination of free beta hCG, PAPP-A, AFP, and nuchal translucency achieved a detection rate of 96% with a false positive rate of 8.4% to 9.9%. Adding in nasal bone increased detection to 98% while reducing false positive rates to 4.1% to 4.7%.Inclusion of dried blood AFP into traditional first trimester screening improves detection while optimizing contingent protocols so that cell-free fetal DNA testing may be offered in a more cost effective manner. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.