Down syndrome (DS) is a common birth defect characterized by the trisomy of chromosome 21. DS affected umbilical cord (UC) of fetuses exhibits altered architecture of the extracellular matrix. Overexpression of chromosome 21 genes encoding the collagen type VI (COLVI) chains α1(VI) and α2(VI), COL6A1 and COL6A2 respectively, was also described for nuchal skin of DS fetuses. The aim of this study was therefore to evaluate the COLVI content in the euploid and DS affected UCs and human skin fibroblasts and to investigate the relation between COLVI with hyaluronan (HA) and hyaluronan synthase-2 (HAS2). We found that the UC of DS fetuses present a denser staining of COLVI and increased COL6A2 gene expression at both early and term gestation. In vitro expression studies in DS-derived fibroblasts showed similarly increased α1(VI) and α2(VI) chains at the protein and transcriptional level, supporting the hypothesis of the gene dosage effect. Furthermore, increased levels of HA and HAS2 were also determined in DS-derived skin fibroblast cultures. Notably, silencing of COL6A2 in DS-derived cells resulted in down-regulation of HAS2 with a simultaneous decrease in secreted HA. Exogenous addition of COLVI to normal fibroblasts did not have any effect on the HAS2 gene expression. Conclusively, UC and skin fibroblasts in DS present a significant increase in COLVI and HA; the overexpression of COL6A2 in the DS tissue and cells is closely related to the increased expression of HAS2 expression. These data may explain the DS phenotypes and the effects in organ tissue maturation. © 2013 The Authors Journal compilation © 2013 FEBS.