BACKGROUND: The intricate and varied clinical presentations of systemic sclerosis (SSc) pose significant challenges for treatment. While several studies have investigated the therapeutic potential of mesenchymal stem cell transplantation (MSCT), the clarity of its long-term outcomes for SSc patients is still lacking. METHODS: Data on MSCT were extracted from the medical records of inpatients at Nanjing Drum Tower Hospital between January 2013 and December 2022. Additionally, Baseline characteristics and survival outcomes were ascertained from medical records and telephone follow-up. Propensity score matching (PSM) was employed to equalize the baseline characteristics of the patient groups, while survival analysis and multivariate Cox regression assessed the relationship between received MSCT and all-cause mortality and disease-specific survival rates in SSc patients. RESULTS: Of the 333 hospitalized SSc patients, 113 patients underwent MSCT. The log-rank test revealed significantly higher survival rates in the MSCT group compared to the control group (10-year survival rate 89.4% vs. 73.4%, P = 0.002). In the PSM cohort, receiving MSCT significantly reduced mortality (10-year survival 88.0% vs. 79.9%, P = 0.032). Multivariate Cox regression analysis indicated that MSCT was linked to a reduced mortality risk during the follow-up period (HR 0.38, 95% CI 0.19-0.75, P = 0.005). This finding was further confirmed in the matched cohort (HR 0.38, 95% CI 0.18-0.82, P = 0.014). Subgroup analyses revealed that treated with MSCT was correlated with reduced mortality in patients of various demographics, including younger age at diagnosis (≤ 47 years), female, diffuse cutaneous systemic sclerosis (dcSSc) subtype, concurrent arthritis, pulmonary arterial hypertension (PAH), and interstitial lung disease (ILD). CONCLUSION: MSCT significantly enhances the survival rate of patients with SSc, with outcomes related to the age at diagnosis. MSCT is particularly indicated for patients with comorbid conditions, including PAH, ILD, digital ulcers, and arthritis, as well as those with severe disease presentations associated with the dcSSc subtype.