Studies in vitro and in mice indicate a role for Coenzyme Q10 (CoQ10) in gene expression. To determine this function in relationship to physiological readouts, a 2-week supplementation study with the reduced form of CoQ10 (ubiquinol, Q10H2, 150 mg/d) was performed in 53 healthy males. Mean CoQ10 plasma levels increased 4.8-fold after supplementation. Transcriptomic and bioinformatic approaches identified a gene-gene interaction network in CD14-positive monocytes, which functions in inflammation, cell differentiation and PPAR-signaling. These Q10H2-induced gene expression signatures were also described previously in liver tissues of SAMP1 mice. Biochemical as well as NMR-based analyses showed a reduction of LDL cholesterol plasma levels after Q10H2 supplementation. This effect was especially pronounced in atherogenic small dense LDL particles (19-21 nm, 1.045 g/l). In agreement with gene expression signatures, Q10H2 reduces the number of erythrocytes but increases the concentration of reticulocytes. In conclusion, Q10H2 induces characteristic gene expression patterns, which are translated into reduced LDL cholesterol levels and erythropoiesis in humans.