Objectives: To assess whether adding placental growth factor (PlGF) or replacing pregnancy-associated plasma protein-A (PAPP-A) improves the first trimester combined test performance for trisomy 21. Design: Prospective observation Cohort Setting: The Chinese University of Hong Kong, China Sample: 11,518 women having a singleton pregnancy screened for trisomy 21 between December 2016 and December 2019 using the first trimester combined test. Methods: PlGF was prospectively measured and estimated term risk for trisomy 21 was calculated by 1) replacing PAPP-A with PlGF and 2) adding PlGF to the combined test which includes nuchal translucency, PAPP-A and free β-human chorionic gonadotropin (hCG). Main Outcome Measure: Screening performance, area under curve (AUC), detection rate (DR), screen positive rate (SPR) and false positive rate (FPR) Results: 29 women had trisomy 21. The combined tests DR, FPR and SPR were 89.7%, 5.7% and 6% respectively. DR when replacing PAPP-A or adding PlGF to the combined test remained unchanged. Replacing PAPP-A by PlGF increased FPR and SPR to 6.2% and 6.4% respectively. Adding PlGF to the combined test gave FPR and SPR rates of 5.5% and 5.7% respectively. Adding or replacing PlGF did not give a significant increase in AUC (p>0.48) over that of the combined test. Conclusion: Adding PlGF to the combined test or replacing PAPP-A with PlGF in the combined test did not improve trisomy 21 detection rate. Replacing PAPP-A by PlGF increased SPR, whilst adding PlGF resulted in only a marginal reduction in SPR.