ProblemCpG oligodeoxynucleotides (ODNs) can induce immunological changes in non‐obese diabetic (NOD) mice and increase embryo loss, but little is known about the mechanism. This study aimed to determine the role of adiponectin in CpG ODN‐induced pregnancy failure.Method of studyOligodeoxynucleotide 1826 was intraperitoneally injected to NOD mice, and ODN 2216, ODN 2006, and ODN 2395 were used to stimulate human trophoblast cell lines to investigate adiponectin expression patterns and its possible effects on trophoblast function.ResultsCpG ODNs downregulated adiponectin via the cJun N‐terminal kinase signaling pathway and led to increased embryo loss (from 6.9 to 33.3%). ODN 2006 impaired human trophoblast cell migration, which was successfully rescued by adiponectin treatment.ConclusionCpG ODNs decreased placental adiponectin expression in NOD mice and impaired human trophoblast function and was associated with increased embryo loss. Adiponectin may therefore play an important protective role in the prevention of bacteria‐induced pregnancy failure.