Objective: To determine whether the mechanism for the retention of interstitial fluid in trisomy 21 fetuses presenting with nuchal translucency at 10–14 weeks' gestation is an alteration in the composition of collagen type VI, which is normally a triple helix formed of three single chains, α1, α2, and α3. The genes responsible for the a1 and a2 chains, COL6A1 and COL6A2, are located on chromosome 21 and therefore may be overexpressed in trisomy 21, whereas COL6A3 is located in chromosome 2. Methods: Skin tissue was obtained after termination of pregnancy at 11–16 weeks' gestation in five fetuses with trisomy 21 and five normal controls. Total RNA was extracted and the steady-state levels of COL6A1 and COL6A3 mRNA expression of the gene transcripts were determined. Additionally, the distribution of collagen type VI in the skin of trisomy 21 and normal fetuses was analyzed using an immunohistochemical method. Results: The ratio of the normalized densitometric scores for the mRNA expression of COL6A1 to COL6A3 in the skin of trisomy 21 fetuses was twice as high as in normal fetuses. Immunohistochemistry demonstrated that in trisomy 21 fetuses collagen type VI formed a dense network extending from the epidermal basement membrane to the subcutis, whereas in normal fetuses dense staining was confined to the upper region of the dermis. Conclusion: The distribution for collagen type VI is different from normal in the skin of trisomy 21 fetuses, and there is overexpression of COL6A1 compared with COL6A3.