Objective: To investigate the clinical efficacy and safety of regimens containing hypomethylating agents (HMAs) in the treatment of intermediate- to high-risk myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN). Methods: A retrospective analysis was performed on 29 patients with intermediate- to high-risk MDS/MPN who received regimens containing HMAs in the hematology department of the First Affiliated Hospital of Nanjing Medical University from November 2012 to January 2022. The patients were divided into the HMAs-treated group and the decitabine combined with low-dose chemotherapy (D-CAG)-treated group, and the clinical remission rate, median overall survival (OS) and leukemia free survival (LFS) of the two groups were compared. Results: A total of 29 MDS/MPN patients including 22 males and 7 females were enrolled, with a median age of 66 years. There were 16 patients in the HMAs-treated group and 13 in the D-CAG-treated group, and the differences in baseline characteristics between the two groups were not statistically significant (P>0.05). There was no significant difference in clinical efficiency between the two groups. Survival analysis showed the median OS of patients in the D-CAG-treated group was significantly longer than that in the HAMs-treated group (26.3 months vs. 13.5 months, P=0.0095). And patients in the D-CAG-treated group had a longer median LFS compared with patients in the HAMs-treated group (24.2 months vs. 8.7 months, P=0.0455). Univariate analysis identified hemoglobin (≥70 vs. < 70g/L) and treatment regimen were prognostic factors for OS, while multivariate analysis showed that only treatment regimen was the independent prognostic factor affecting OS. The main adverse effects in both groups were grade 3-4 myelosuppression, pulmonary infection, and fever (the infection focus was not identified). The D-CAG-treated group was more prone to grade 3-4 myelosuppression compared with the HAMs-treated group, but the risk of infection in patients did not increase. Conclusions: D-CAG regimen is safe and effective in MDS/MPN patients, and may bring survival benefit, which will provide a reference for clinical treatment.