Background A better understanding of the molecular mechanisms involved in papillary thyroid cancer (PTC)-associated adverse outcome is needed to effectively manage these patients. Our objectives were to identify molecular pathways associated with unfavorable features and outcome in patients with PTC. Method We performed genome-wide expression (GWE) analysis in 64 PTC human tissue samples. Clinical, pathologic and microarray data were analyzed to identify differentially expressed genes/pathways associated with an unfavorable outcome. Gene Set Enrichment Analysis (GSEA) was used to determine which molecular pathways are associated with mortality. Results GWE analysis identified 43, 115 and 40 genes that were significantly differentially expressed by gender, tumor differentiation status and mortality, respectively, with a false discovery rate (FDR) of <5%. For mortality, GSEA revealed 7 enriched pathways including transfer RNA synthesis, mitochondria and oxidative phosphorylation, porphyrin and chlorophyll metabolism, and fatty acid synthesis. Leading edge analysis showed 341 genes significantly involved in the enriched pathways. Cluster analysis using 100 differentially expressed genes showed complete separation of patients by mortality. Conclusions To our knowledge, this is the first GWE analysis of PTC and adverse outcome. Eleven molecular pathways were significantly associated with PTC mortality. A 100-gene signature completely separates patients with and without PTC-associated mortality.