OBJECTIVE The aim of this study is to identify potential biomarkers for fetal trisomy 21 from previous publications using proteomic techniques and examine the potential value of such biomarkers in early screening for this aneuploidy. METHODS This was a case-control study of 25 pregnancies with fetal trisomy 21 and 50 euploid controls undergoing first-trimester screening for aneuploidies by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free β-human chorionic gonadotrophin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). The maternal serum concentrations of afamin, apolipoprotein E, clusterin, ceruloplasmin, epidermal growth factor, fetuin-A, pigment epithelium-derived factor glycoprotein and transthyretin were determined using an ELISA and compared in the euploid and trisomy 21 groups. RESULTS In pregnancies with fetal trisomy 21, the median maternal age, fetal NT thickness and serum free β-hCG were increased, whereas serum PAPP-A was decreased. However, there were no significant differences between cases and controls in any of the biomarkers. CONCLUSION Proteins identified as potential biomarkers for trisomy 21 using proteomic techniques have not been found to be useful in early screening for this aneuploidy.