BACKGROUND Hypomethylating agents (HMA) are considered the first-line therapy for high-risk myelodysplastic syndromes (MDS). However, as the efficacy and safety of rational dosing regimens are lacking, we evaluated the effectiveness and safety of reduced-dose azacitidine (AZA) vs. decitabine (DAC) in adult MDS patients. MATERIAL AND METHODS This retrospective study was conducted at the Institute of Hematology & Blood Diseases Hospital, for hospitalized MDS patients diagnosed (WHO 2008 classification criteria) from May 2006 to February 2020. These AZA- and DCA-naive patients treated with AZA 100 mg/(m²·day) for 5 days to 7 days or DAC 20 mg/(m²·day) for 3 days to 4 days, or 20 mg/(m²·day) 1 day/week for 3 weeks/month were assessed for treatment responses and adverse events. RESULTS Of the 158 enrolled MDS patients, 120 and 38 patients were administered reduced-dose DAC and AZA, respectively. All the patients received a median of 2 treatment cycles. The overall response rates (ORR) were 50.0% and 73.3% in the AZA and DAC groups, respectively (P=0.007). The percentage of platelet transfusion dependence in the AZA group was lower than the DAC group (P=0.026). The multivariate analysis demonstrated that the DAC treatment was a significant factor for improved responses (OR 2.928; 95% CI 1.267-6.896; P=0.012), and the absolute neutrophil count (ANC) was a predictor of the ORR (OR 0.725; 95% CI 0.558-0.898; P=0.008). Neutropenia (P=0.016) and infection (P=0.032) incidences were higher in the DAC group. CONCLUSIONS The reduced-dose DAC group demonstrated a better response than the AZA group in MDS patients with different prognostic risks. The patients’ pre-treatment ANC was a significant factor associated with the ORR.