AbstractBackgroundFirst‐trimester maternal serum screening for Down syndrome (DS) can be improved by the use of additional serum markers. We examined whether progesterone (P), synthesized by placenta, might be a first‐trimester maternal serum marker for fetal DS.Materials and MethodsP was quantified in first‐trimester maternal serum from 42 DS, six trisomy 18 and two trisomy 13 pregnancies and 115 controls. Log‐regression of P versus gestational age in days was used to convert P concentrations into multiples of the median (MoM).ResultsThe P concentrations in controls increased with gestational age (p = 9.5 × 10−7). The log10MoM P distribution in DS pregnancies was not significantly different from that in controls. However, from day 58–67, the log10MoM P was elevated in DS pregnancies (n = 10) with a mean (SD) of 0.1040 (0.0956), compared to a mean (SD) of − 0.0109 (0.1661) in controls (n = 24) (p = 0.05). Five out of six trisomy 18 and both trisomy 13 pregnancies had a P MoM < 1.ConclusionP is not a useful marker for DS in first trimester, except perhaps in a narrow gestational age window from day 58 to 67. P is a trisomy 18/13 marker. Copyright © 2008 John Wiley & Sons, Ltd.