Background Immunotherapy has revolutionized cancer treatment, with FDA approvals and NCCN guidelines incorporating immune checkpoint inhibitors across over 20 malignancies. Despite its growing use and preference over chemotherapy, data on immunotherapy-related complications leading to hospital readmissions remain limited. No large retrospective cohort study has yet addressed this gap Methods We conducted a retrospective cohort study using the 2022 Nationwide Readmissions Database (NRD). Index admissions involving inpatient immunotherapy were identified using ICD-10 code Z51.12, and 90-day all-cause readmissions were tracked. Survey-weighted logistic, linear, and Cox proportional hazards models were used to compare baseline characteristics and identify predictors of 90-day readmission Results A total of 2,394 weighted admissions met criteria as index immunotherapy admissions, with a 90-day readmission rate of 41.06% (95% CI: 36.7–47.2%). There were 983 weighted 90-day readmissions. Mean index LOS was 10.1 days, with a cumulative LOS of 24,222 days. The average total hospital charge for index admissions was $692,011, and the mean cost was $161,506, yielding a total cost burden of ~$379 million. Among readmitted patients (n ≈ 961 weighted), mean LOS was 8.7 days (8,510 total days), with a mean cost of $114,195 and cumulative cost burden of ~$110 million. © 2025 American Medical Association. All rights reserved. Primary payer distribution differed between groups (p = 0.0002): Medicare was most common among index admissions (51.7%), while Medicaid was more prevalent in readmissions (16.1% vs. 7.1%). Most care occurred in urban teaching hospitals (95.3% vs. 98.0%). Discharge disposition varied slightly (p = 0.047), with most patients discharged home; transfers and home health use were more common in readmissions.Multivariable Cox regression identified the following significant predictors of 90-day readmission: younger age (HR=0.983, p=0.000), self- pay status (HR=2.82), Addison’s disease (HR=4.58), hyperthyroidism (HR=5.59), Crohn’s disease (HR=7.13), COPD (HR=2.00), and others.Top non-cancer, non-chemotherapy readmission diagnoses included neutropenia (79.1), sepsis (55.1), immune effector therapy complications (32.5), COVID-19 (32.1), infusion complications (23.4), anemia of chronic disease (21.8), ABO incompatibility (10.4), AKI (9.0), transplant complications (8.6), and bacteremia (8.4) Conclusion Inpatient immunotherapy is associated with a high 90-day readmission rate and substantial healthcare costs. Readmission risk is influenced by insurance type and specific comorbidities, offering targets for intervention to reduce preventable hospitalizations in this expanding population