Although somatic cell nuclear transfer (SCNT) cloning is more efficient in cattle than in any other species tested so far, there is a high rate of pregnancy failure that has been linked to structural and functional abnormalities of the placenta. We tested the hypothesis that these changes may originate from disturbed embryo-maternal interactions in the peri-implantation period. Therefore, we evaluated the response of the endometrium to SCNT embryos (produced from 7 different fetal fibroblast cell lines) as compared with embryos derived from in vitro fertilization (IVF). SCNT embryos and IVF embryos were cultured under identical conditions to the blastocyst stage (day 7) and were transferred to corresponding recipients, which were slaughtered at day 18 of pregnancy. The mRNA profiles of endometrium samples were obtained using a custom cDNA microarray enriched for transcripts differentially expressed in the endometrium and/or oviduct epithelium during the estrous cycle and/or early pregnancy. Overall, the variation in mRNA profiles was greater in the SCNT group than in the IVF group. Furthermore, 58 transcripts were differentially abundant in endometria from SCNT and IVF pregnancies. Prominent examples are orphan nuclear receptor COUP-TFII and connexin 43, both known to play important roles in uterine receptivity and conceptus placentation. These findings suggest that placental failure in bovine clone pregnancies may originate from abnormal embryomaternal communication that develops during the peri-implantation period. Endometrium transcriptome profiles may serve as a tool to evaluate SCNT embryos for their ability to establish pregnancy and develop a functional placenta.Bos taurus ͉ cloning ͉ early pregnancy ͉ gene expression ͉ microarray C loning by somatic cell nuclear transfer (SCNT) (1) is an important strategic tool for animal breeding and biotechnology. For example, animals carrying rare desired alleles can be multiplied to introduce the desired allele into the breeding population. The life span and capacity of valuable breeding animals and the physiologically limited number of offspring of female animals can be increased, thus enhancing selection intensity. Moreover, cloning allows the propagation of desired genotypes without the risk of genetic recombination that is inherent to sexual reproduction. In animal biotechnology, SCNT using genetically modified donor cells is a powerful approach for the generation of transgenic animals (2) and so far is the only technique facilitating targeted mutagenesis in livestock species (3). Moreover, cloning can be used to multiply transgenic animals and to propagate multitransgenic individuals without segregation of the individual transgenes.Despite the plethora of important applications of cloning, the efficiency of this technology still is very low. Although SCNT is more efficient in cattle than in any other species tested so far, a recent survey covering the results of bovine cloning in Brazil, Argentina, and the United States over a 5-year period revealed that only 9...