The objective was to examine the applicability of the two biochemical markers PAPP-A and free beta-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 6-14. 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 8-10 and weeks 11-14. 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 8-10 and 0.531 in weeks 11-14. On the contrary, free beta-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.