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Background: The AML60+ score has been proposed for risk stratification in intensively treated elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic neoplasms (MDS). Its prognostic impact in patients treated with hypomethylating agents (HMA) is unknown. Methods: Patients ≥ 60 years of age diagnosed with AML or MDS/AML according to ICC2022 were eligible for this retrospective and multicenter chart review if they had received at least one cycle of HMA-based treatment. Results: A cohort of 142 patients was analyzed. During follow-up (median 8 months), 114 patients died. The molecular Prognostic Score (mPRS) was available for 121 patients, the European Leukemia Net (ELN) 2022 classification for 117 patients, and the AML60+ for 105 patients. According to AML60+, 33 patients (31.4%) were classified as very poor risk, 36 (34.3%) as poor risk, and 34 (32.4%) as intermediate risk. Two patients (1.9%) were classified as favorable. Median overall survival (OS) was 21.7 months (mo) for the combined intermediate/favorable group, 7 mo for the poor risk group and 3 mo for the very poor risk group (p < 0.0001). Cox regression analysis (reference category: very poor) showed a significantly lower risk of death for both intermediate/favorable risk patients (HR 0.17, 95% CI 0.10–0.31, p < 0.001) and poor risk patients (HR 0.47, 95% CI 0.28–0.78, p = 0.004). The concordance score was 0.67 for AML60+, 0.60 for mPRS, and 0.58 for ELN2022. Conclusions: The AML60+ may represent a useful prognostic tool for elderly AML patients treated with HMA-based therapies. In particular, it could help to identify a group with a relatively favorable prognosis that is not clearly identified by the ELN2022 or the mPRS risk classification. However, analyses of larger cohorts are necessary to confirm our findings.