Background: The Sry-related high-mobility-group box (SOX) gene family, with 20 known transcription factors in humans, plays essential roles during development and in many disease processes. Several SOX proteins, e.g., SOX4, SOX11, and SOX9, are required for normal heart morphogenesis. SOX9 was shown to contribute to cardiac fibrosis in animal models. However, differential expression of other SOX transcription factors and their functional roles in the failing human myocardium have not been explored. Methods and Findings: All 20 SOX genes from RNA-seq data were extracted, and their RNA levels were compared to the NF, DCM, and hypertrophic cardiomyopathy (HCM) groups. The protein levels of the differential expressed SOX genes were confirmed by Western blot. Four SOX genes whose RNA levels were significantly upregulated in DCM or HCM compared to NF. However, only SOX4 and SOX8 proteins were markedly increased in the heart failure groups. Gene co-expression network analysis identified genes associated and respond similarly to perturbations with SOX4 in cardiac tissues. Using a meta-analysis combining epigenetics and genome-wide association data, we reported several genomic variants associated with HF phenotype linked to SOX4 or SOX8. Conclusions: Elevation of SOX8 and SOX4 are observed in the failing human myocardium. The molecular mechanism associated with them in HF warrants further investigation.