Introduction Systemic sclerosis (SSc) is a connective tissue disease with multi-system involvement and it has an increased risk of developing hematologic malignancies. This study aims to report the association between hematologic malignancies with SSc and to characterize in-hospital demographics and outcomes in patients with hematologic malignancies with and without SSc. Methods We performed a retrospective review of pooled data from the National Inpatient Sample (NIS) database from 2016 to 2020. Crude prevalence of hematologic malignancies among hospitalized patients with and without SSc was calculated. Logistic regression was used for statistical significance of differences in prevalence while adjusting for confounders. Demographic characteristics and outcomes of patients with hematologic malignancies with and without SSc was compared. Statistical analysis was done using chi-square and multivariate logistic regression. Results Among all adult hospitalizations, the prevalence of hematologic malignancy was 1.87% compared to 2.66% among patients with SSc (adjusted odds ratio (aOR) 1.52, p <0.01). Relative to the non-SSc group, the SSc group had higher odds of in-patient mortality (OR 1.43; 95% confidence interval (CI) 1.11 – 1.87; p<0.01). The prevalence of lymphoma was 0.71% compared to 1.04% among patients with SSc (aOR 1.6, p < 0.01). Relative to the non-SSc group, the lymphoma-SSc group had similar odds of in-patient mortality (OR 0.93; 95% CI 0.55 – 1.59; p=0.80). The prevalence of leukemia was 0.79% compared to 1.28% among patients with SSc (aOR 1.74, p < 0.01). The leukemia-SSc group had higher odds of in-patient mortality (OR 1.78; 95% CI 1.29 – 2.46; p<0.01). For myeloma, there was no difference in the prevalence in adults with and without SSc (0.4 vs. 0.38%, aOR 0.96, p=0.64) and there was no difference of in-hospital mortality. Conclusions There is a positive significant association between hematologic malignancies including lymphoma and leukemia, and SSc. This association was not seen between myeloma and SSc. There is increased in-hospital mortality of patients with leukemia and SSc.