In this study, we have investigated the expression of 87 micro (mi)RNAs in activated CD4(+) T cells cultured in the presence or absence of the immunoregulatory molecule soluble HLA-G (sHLA-G). We observed (i) a decreased miR-451 expression and (ii) an increased miR-210 expression in sHLA-G-treated CD4(+) T cells. By transfecting CD4(+) T cells with miR-210 and miR-451 mimics or inhibitors, we found that sHLA-G-mediated modulation of these miRNAs was not related to sHLA-G-mediated inhibition of (i) proliferation and (ii) CXCR3 expression in CD4(+) T cells. Finally, we investigated the expression of 14 genes targeted by miR-210 or miR-451 in activated CD4(+) T cells, treated or not with sHLA-G. We observed an increased expression of OSR-1 (odd-skipped related 1) and HBP-1 (HMG-box transcription factor 1) and a decreased expression of CXCL16 (chemokine C-X-C motif ligand 16) and C11orf30 (chromosome 11 open reading frame 30) in sHLA-G-treated CD4(+) T cells. In conclusion, sHLA-G triggered a modulation of miRNA expression that may in turn modulate downstream gene expression, thus affecting CD4(+) T-cell function.