Aims: Sjögren’s syndrome (SS) is a systemic autoimmune disease with poorly characterized hospitalization outcomes in the United States. We aimed to characterize hospitalization trends, comorbidity profiles, organ-specific manifestations, predictors of in-hospital mortality, and racial, socioeconomic, and hospital-level disparities among SS-associated hospitalizations using the NIS 2016–2020 dataset. Methods: Retrospective cross-sectional analysis of the NIS (2016–2020). Adults with SS (ICD-10-CM M35.00–M35.0C) were identified across 40 diagnosis fields and matched 3:1 with non-autoimmune controls by age, sex, and year. Survey-weighted analyses included bivariate comparisons, Elixhauser comorbidity profiling, organ-specific phenotyping, nested multivariable logistic regression for mortality predictors, and adjusted disparities analyses using predictive margins. Results: Among 272,630 weighted SS-associated hospitalizations (91.4% female, mean age 64.2 years), extraglandular manifestations were documented in 33.8%. Despite a significantly higher baseline comorbidity burden compared with 817,890 matched control hospitalizations, SS-associated admissions exhibited paradoxically lower crude in-hospital mortality (2.13% vs. 2.59%, p<0.001). However, within the SS cohort, acute complications were associated with substantial mortality risk in the fully adjusted model: independent predictors included mechanical ventilation (OR 21.08), sepsis (OR 2.80), stroke (OR 2.78), malignancy (OR 2.46), and interstitial lung disease (OR 2.10). Significant disparities persisted after multivariable adjustment: Asian/Pacific Islander hospitalizations had higher mortality odds (OR 1.67, p=0.002) and incurred $22,643 more in adjusted charges compared with White hospitalizations. Self-pay or uninsured status was associated with doubled mortality odds (OR 2.01, p<0.001). Conclusions: Enhanced clinical phenotyping underscores that Sjögren's syndrome is a complex, multisystem disease with a substantial inpatient burden. While SS-associated hospitalizations present with high baseline comorbidities, in-hospital mortality is strongly associated with acute complications, particularly respiratory failure, sepsis, stroke, and interstitial lung disease. Future clinical pathways should prioritize vigilant management of these vulnerabilities while addressing the structural and socioeconomic disparities associated with unequal outcomes.