Myelodysplastic neoplasms (MDS) are a heterogeneous group of clonal disorders of hematopoietic stem cells, characterized by morphological dysplasia in the bone marrow, ineffective hematopoiesis, peripheral blood cytopenias, and a risk of progression to acute myeloid leukemia (AML). Next-generation sequencing (NGS) has contributed to elucidating the pathogenesis of MDS through the identification of molecular drivers and secondary genetic events. While approximately 50% of MDS patients present chromosomal alterations, over 90% have somatic mutations detected. Several studies have shown that somatic mutations are important prognostic biomarkers. The Revised International Scoring System (IPSS-R) is the most used tool for risk stratification in MDS. The treatment of MDS is based on stratifying patients into low-risk (IPSS-R ≤ 3.5, i.e., very low, low, or intermediate) versus high-risk MDS (IPSS-R ≥ 4.0, i.e., intermediate, high, or very high risk). The IPSS-R is based on hematological and cytogenetic features but does not include molecular data. In 2022, the Molecular IPSS (IPSS-M) was developed, considering hematological, cytogenetic, and somatic mutations parameters in 31 genes. In this context, this study compared the risk stratification results in 13 MDS patients using the IPSS-R and IPSS-M tools. All patients had karyotype and NGS (panel of 40 genes) results performed on bone marrow samples. The average age of the patients was 69 years, and the median survival was 18 months. Eight (61.5%) patients had a normal karyotype. The detected cytogenetic alterations were: complex karyotype, del(9q), and -Y. In 10 patients (76.9%), between 1 to 5 mutations (average of 2.1 mutations) in 12 genes were detected, with TP53 and TET2 genes being the most frequently mutated. The VAF (variant allele frequency) of the identified mutations was >5%. The IPSS-R classified eight patients (61.5%) as low risk (IPSS-R < 3.5), with three patients (37.5%) being reclassified by IPSS-M. In these cases, mutations were identified in at least two genes, with ASXL1, BCOR, and IDH2 being prominent, which are associated with a worse prognosis. In one of these cases, an SF3B1 mutation, associated with a good prognosis, was also identified but was co-occurring with DNMT3A and JAK2 mutations. Five patients (38.5%) were classified as high risk by IPSS-R (IPSS-R > 4.0), and IPSS-M reclassified one high-risk patient to very high risk and one intermediate-risk patient to very high risk. In these cases, mutations were also identified in genes associated with adverse prognosis, such as ASXL1, BCOR, RUNX1, STAG2, and U2AF1. It should be emphasized that in cases reclassified by IPSS-M, mutations in genes frequently mutated in MDS were identified. The investigation of gene mutations is important in identifying patients at high risk of progression to AML, allowing for early aggressive therapy. Genomic tests are still costly tools and, therefore, limited to a small portion of MDS patients, limiting the applicability of IPSS-M.