The introduction of hypomethylating agents in the treatment of myelodysplastic syndromes (MDS) has significantly changed the clinical scenario of these diseases, which afflict predominantly older individuals. However, some concerns regarding the optimal application of these innovative and costly agents in the treatment of geriatric high-risk MDS remain. We report here the case of a nonagenarian treated with hypomethylating agents achieving a long-lasting clinical response and a significant improvement in her functional status. Our case confirmed that functional status and biological status, rather than the chronological age alone, can substantially guide the plan of an appropriate treatment strategy in high-risk MDS patients; moreover, the current case emphasizes the need for targeted studies in the field of geriatric MDS in order to formulate guidelines on the appropriate use of these costly agents, so that candidate patients can receive adequate treatment to preserve their quality of life and life expectancy, but at the same time avoiding unnecessary costs deriving from the use of high-cost drugs for those in whom a significant therapeutic result cannot be reasonably expected.