We profiled gene expression at the maternal-fetal interface during the second trimester of pregnancy (13-22 wks) in trisomy 13 (T13; Patau syndrome, n = 4), trisomy 18 (T18; Edwards syndrome, n = 4), trisomy 21 (T21; Down syndrome, n = 8), and in euploid pregnancies (n = 4). FISH confirmed the ploidy of the samples. Global transcriptional profiling identified differentially expressed transcripts ( 2-fold) in T21 (n = 160), T18 (n = 80), and T13 (n = 125). The majority were upregulated. Unexpectedly, most of the misexpressed genes were not located on the relevant trisomic chromosome, suggesting genome-wide dysregulation. A much smaller proportion of the differentially expressed transcripts were encoded on the aneuploid chromosome, also implicating gene dosage (1-5). In T21, <10% of the genes were transcribed from that chromosome, all but one from the Down syndrome critical region (21q21-22), which is postulated to play an important role in the clinical phenotype. For T13 and T18, a higher proportion of the overexpressed genes were located on the trisomic chromosome. In T13, 15% of the upregulated genes were on the affected chromosome; 15 resided on the long arm, 13q11-14. In T18, the percentage increased to 24, 15 of which were also located on the long arm (18q11-22). Our data suggested that the placental (and possibly fetal) phenotypes that are associated with T13, T18 and T21 are driven by the combined effects of genome-wide phenomena and increased gene dosage from critical regions of the triploid chromosome.