The objective of this study was to perform a systematic review of published literature on differentially expressed genes (DEGs) in human epicardial adipose tissue (EAT) to identify molecules associated with CVDs. A systematic literature search was conducted in PubMed, SCOPUS, and ISI Web of Science literature databases for papers published before October 2014 that addressed EAT genes and cardiovascular diseases (CVDs). We included original papers that had performed gene expressions in EAT of patients undergoing open-heart surgery. The Reporting Recommendations for Tumor Marker Prognostic Studies (PRIMARK) assessment tool was also used for methodological quality assessment. From the 180 papers identified by our initial search strategy, 40 studies met the inclusion criteria and presented DEGs in EAT samples from patients with and without CVDs. The included studies reported 42 DEGs identified through comparison of EAT-specific gene expression in patients with and without CVDs. Among the 42 DEGs, genes involved in regulating apoptosis had higher enrichment scores. Notably, interleukin-6 (IL-6) and tumor protein p53 (TP53) were the main hub genes in the network. The results suggest that regulation of apoptosis in EAT is critical for CVD development. Moreover, IL-6 and TP53 as hub genes could serve as biomarkers and therapeutic targets for CVDs.