To investigate whether secretion of soluble human leukocyte antigen- G (HLA- G) by human embryos is associated with embryo development and IVF pregnancy outcome. Retrospective study. In vitro fertilization program affiliated with a university research center. Infertile couples attending an IVF program were selected. Embryo culture conditioned medium (72 hours)- from cases in which intracytoplasmic sperm injection was used for fertilization. Soluble HLA- G in embryo culture medium samples from IVF patients was assayed and associations between soluble HLA- G secretion and outcome measures were analyzed. Two hundred seventy of 386 samples had detectable soluble HLA- G. Soluble HLA- G secretion was independent of embryo grade or patients’ age. The cleavage rate of embryos secreting soluble HLA- G was significantly higher than that of those lacking it (blastomere number 6.71 ± 0.09 vs 5.86 ± 0.22). The live birth rate from embryos with soluble HLA- G was significantly higher than that of those without (48.4% vs. 17.1% , χ 2 = 9.09). Combining soluble HLA- G detection and cleavage rate was most predictive of pregnancy. Our five conclusions are as follows: [1] embryonic secretion of soluble HLA- G protein is variable, [2] secretion of HLA- G is correlated with a higher cleavage rate, [3] secretion of HLA- G is associated with a higher pregnancy rate, [4] HLA- G secretion is a better independent predictor than cleavage rate alone, and [5]- the combination of soluble HLA- G detection and high cleavage rate was the best predictor of outcome. To investigate whether secretion of soluble human leukocyte antigen- G (HLA- G) by human embryos is associated with embryo development and IVF pregnancy outcome. Retrospective study. In vitro fertilization program affiliated with a university research center. Infertile couples attending an IVF program were selected. Embryo culture conditioned medium (72 hours) - from cases in which intracytoplasmic sperm injection was used for fertilization. Soluble HLA- G in embryo culture medium samples from IVF patients was assayed and associations between soluble HLA- G secretion and outcome measures Two hundred seventy of 386 samples had detectable soluble HLA- G. Soluble HLA- G secretion was independent of embryo grade or patients’ age. The cleavage rate of embryos secreting soluble HLA- G was significantly higher than that of those lacking it (blastomere number 6.71 ± 0.09 vs 5.86 ± 0.22). The live birth rate from embryos with soluble HLA-G was significantly higher than that o Combining soluble HLA-G detection and cleavage rate was most predictive of pregnancy. Our five conclusions are as follows: [1] embryonic secretion of soluble HLA-G protein is variable, [2] secretion of HLA-G is correlated with higher cleavage rate, [3] secretion of HLA- G is associated with a higher pregnancy rate, [4] HLA-G secretion is a better independent predictor than cleavage rate alone, and [5] - the combination of soluble HLA-G detection and high cleavage rate was the best predictor of outcome.