Abdominal aortic aneurysms (AAAs) are a prevalent and deadly human pathology with strong sexual dimorphism. Research demonstrates that sex hormones influence, but do not fully explain, male versus female AAA pathology. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, for the first time, we defined the effect of female (XX) versus male (XY) chromosome complement on AAA formation and rupture in phenotypically female mice using an established murine model. Abdominal aortas from female mice bearing the XY chromosome selectively expressed Y chromosome genes, while genes known to escape X-inactivation were higher in XX females. The majority of gene differences in XY females fell within inflammatory pathways. When XY females were infused with AngII, AAA incidences doubled and aneurysms ruptured. AAAs from XY females exhibited significant inflammation. Moreover, infusion of AngII to XY females augmented aortic activity of matrix metalloproteinases. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to XX females. These results demonstrate that an XY sex chromosome complement profoundly influences aortic gene expression profiles and promotes AAA severity. Overall design: Phenotypically female Ldlr-/- mice with an XX or an XY sex chromosome complement were used. XY animals were made phenotypically female as follows: male sires had the Sry gene responsible for testes development knocked out of the Y chromosome and knocked in to automal chormosomes. During sexual reproduction, XY progeny that did not receive the autosomal Sry gene developed into phenotypical and reproductively intact females. At 8 weeks of age; XX (n = 10) and XY (n = 10) subjects underwent sham surgery or ovariectomy (OXV), yielding four treatment groups- XX Sham (n = 5); XX OVX (n = 5); XY Sham (n = 4); and XY OVX (n = 6). After two weeks of recovery, mice were fed the Western high fat diet for one week. Animals were then killed and aortas were dissected under a dissecting microscope and placed in RNA later solution (Ambion, cat#AM7021). Abdominal aortas (diaphragm to the ileac bifurcation) were used for RNA extraction. RNA was extracted using the Rneasy fibrous tissue mini kit (Qiagen, cat#74704), and the RNA concentration and quality was quantified by Agilent 2100 bioanalyzer using RNA 6000 Nano labchip kit (Agilent Technologies, Cat# 5067-151). Harvested abdominal aortic RNA samples (n = 20) were of sufficient quantity and quality that did not differ significantly among treatment groups (Agilent Bioanalyzer RNA Integrity Number [RIN]: 9.51 ± 0.07 – p = 0.25; [RNA] (ng/ul): 39.5 ± 3.4 – p = 0.93; 28s:18s ratio: 2.83 ± 0.89 – p = 0.33-; all statistical tests by ANOVA). Extracted RNA was labeled and hybridized to Affymetrix Mouse Transcriptome Assay 1.0 arrays (one array per subject/ aorta). Signal intensities were calculated using the RMA algorithm at the transcript level in Genomics Suite (Partek, St Louis). Data were transferred to flat files in Excel and associated with vendor-provided April 2015 annotation data. Pre-statistical filtering retained unique, annotated probe sets with adequate signal intensity (signal intensity ≥ 4.2 on at least 4 arrays in the study). Filtered signal intensities were analyzed by two-way ANOVA to identify significant main effects of genotype (XX versus XY), surgery (Sham vs OVX), as well as interaction. The False Discovery Rate (FDR) procedure was used to estimate the error of multiple testing.