Colon cancer is a major cause of cancer mortality worldwide and most colon cancers are adenocarcinoma. MicroRNA (miRNA) expression signature has been shown to be able to predict progression and prognosis of various cancers. The aim of our study was to explore a novel signature of microRNA expression for predicting survival of colon adenocarcinoma patients. By analyzing the miRNA expression profiles and clinical information of 329 colon adenocarcinoma patients derived from The Cancer Genome Atlas database. 129 miRNAs were identified to be expressed differentially between the cancer and adjacent tissues. Among them, 27 miRNAs were found to be associated with the corresponding clinical characteristics of the patients. Furthermore, 7 miRNAs (let-7a-2, mir-32, mir-181a-1, mir-197, mir-328, mir-505 and mir-652) were found to be significantly correlated with the patient survival. The risk established by the 7-miRNA signature we built was proved be an independent prognostic factor (Hazard ratio [HR] = 2.048; 95% CI = 1.144-3.664; p, 0.016). In summary, our study identified miRNAs correlated with progression and prognosis of colon adenocarcinoma and built a 7-microRNA expression signature for prediction of the survival of the patients with colon adenocarcinoma.