Immune tolerance of the semi-allogeneic fetus requires CD4+FOXP3+ T-regulatory (Treg) cells, which suppress inflammation and anti-fetal immunity. Paternal antigen-specific Treg cells expand at the outset of pregnancy in response to signals in seminal fluid. Recent studies demonstrate that microRNAs (miRNA) including miR-155 play an important role in Treg development and function. This study aimed to assess the contribution of maternal miR-155 to Treg cell induction in early pregnancy, by evaluating Treg cell number and phenotype using flow cytometry in miR-155-/- and miR-155+/+ (C57Bl/6) females at estrus, and d3.5pc after mating with Balb/c males (n=11-13 / group). On d3.5pc, there was a substantial reduction in the percentage (2.3-fold, p<0.001) and total number (3.5-fold, p<0.001) of Treg cells in miR-155-/- compared to miR-155+/+ mice. This was attributable partly to a smaller baseline Treg cell pool at estrus, and partly to a lower proliferative response to mating, associated with fewer CD11c+ dendritic cells required for Treg cell activation. Moreover, Treg cell Foxp3 intensity was diminished in miR-155-/- compared to miR-155+/+ mice (d3.5pc, 1.5-fold, p<0.001), consistent with impaired suppressive competence. Additional miR-155-/- and miR-155+/+ mice (n=20-21 / group) were administered low dose LPS (1.0 ug) on d9.5pc, to evaluate impact of miR-155 deficiency on inflammation-induced fetal loss. Fewer miR-155-/- mice carried viable fetuses (11/21 in miR-155 -/- vs. 20/20 in miR-155 +/+, p< 0.05) and viable fetuses per mated female were reduced on d17.5pc by 67% (mean±SEM = 2.5±0.6 in miR-155-/- vs. 7.5±0.4 in miR-155+/+, p< 0.001). Thus, miR-155 deficiency causes a reduced Treg cell pool in early pregnancy and imparts elevated susceptibility to inflammatory challenge in mid-gestation. These data indicate a key role for miR-155 in Treg cell-mediated protection from inflammatory challenge in pregnancy. This finding may be relevant to understanding the molecular regulation of Treg cells in immune-mediated gestational disorders in women.