The objective was to examine the applicability of the two biochemical markers PAPP-A and free β-hCG for fetal trisomy 21 (T21) in very early pregnancy: gestational weeks (GA) 6 and 7. Medians for the two markers were generated on 36,745 fetal T21 unaffected pregnancies from gestational weeks 614. Concentrations were converted to Multiples of the Medians (MoMs). Median MoM from T21 affected pregnancies were compared over three intervals of gestational age; the very early weeks 6 and 7, weeks 810 and weeks 1114. Median MoM from 9 affected pregnancies with a very early blood sample had a PAPP-A median MoM of 0.269, compared to 0.392 in weeks 810 and 0.531 in weeks 1114. On the contrary, free β-hCG diverged from the median with increasing gestational age. Our data suggest that PAPP-A is a useful marker for very early testing in first trimester screening for fetal T21.