To our knowledge, the feasibility of therapy with hypomethylating agents (HAs) in patients with renal insufficiency (RI) has not been examined.We reviewed 41 patients with a diagnosis of acute myeloid leukemia (n = 17), myelodysplastic syndromes (n = 15), and chronic myelomonocytic leukemia (n = 9) who had RI and were receiving therapy with azacitidine or decitabine. The median number of administered cycles was 3. Most patients (39; 95%) received a standard dose of the drugs at the initiation of therapy. Nine patients (22%) required treatment interruptions or discontinuation, and 10 patients (24%) required dose reductions.The overall response rate was 63%, and 4 patients (10%) achieved a complete response. Twenty patients (51%) experienced grade 3 or 4 myelosuppression-related toxicities. Hospitalization was required in 68% of the patients. Among 12 patients with an estimated glomerular filtration rate of 29 mL per minute or less, 6 required dose reductions attributable to myelosuppression (n = 3) or to worsening renal function (n = 3). The overall survival (OS) at 18 months was 12%, and the median OS was 8.6 months.The use of HA in patients with RI is feasible, but is associated with a higher incidence of toxicity. Dose adjustments and the use of growth factor may be necessary for some patients.