The management of myelodysplastic syndromes (MDS) in elderly patients is a significant clinical problem. The therapeutic options range from observation alone for patients with low-risk disease, lenalidomide for patients with 5q-syndrome, to 5-azacytidine (5-AZA) for patients with higher risk of disease. In this paper, we summarize the clinical course of three patients with high-risk MDS treated with 5-AZA as well as the management and supportive care measures for adverse events. As expected, based on available clinical trials data, the agent resulted in clinical and hematological improvement in these patients with acceptable side effects. 5-AZA is an attractive option for elderly patients with high-risk MDS.