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Abstract Introduction Diffuse large B-cell lymphoma accounts for one of the highest annual death rates among non-Hodgkin lymphomas, with close to 5,600 deaths and a mortality rate of 1.7 per 100,000 in the USA between 2018–2022. Several factors have contributed to worse hospital outcomes and early mortality. There appears to be a gap in knowledge regarding the various comorbidities and hospital- and patient-level characteristics that may play a role. Through this study, we aim to identify statistically significant associations of such predictors with early readmissions, which can be used to guide strategies to mitigate the high mortality rate among patients suffering from this disease.Method We conducted a retrospective analysis of the 2022 Nationwide Readmissions Database (NRD), part of the Healthcare Cost and Utilization Project (HCUP). Hospitalizations with a diagnosis of diffuse large B-cell lymphoma (DLBCL) were identified and categorized into index admissions and 90-day readmissions. Survey-weighted logistic, linear, and Cox proportional hazards regression models were used to compare clinical and hospital-level characteristics and identify predictors of 90-day readmission.ResultsA total of 22,805.7 weighted patients met eligibility criteria and were categorized as index admissions. Among these, 9,154.5 patients (43.2%; 95% CI: 41.9%–44.5%) experienced at least one readmission within 90 days. The mean length of stay (LOS) was 10.3 days for index admissions and 9.9 days for readmissions. Mean hospital charges were $197,414 for index admissions and $177,659 for readmissions; corresponding mean costs were $49,232 and $44,183, respectively. The cumulative hospitalization burden of 90-day readmissions amounted to 90,694 days, total hospital costs of $401 million, and total charges of approximately $1.61 billion.Excluding DLBCL-related and chemotherapy/immunotherapy follow-up codes, the most common primary diagnoses for 90-day readmissions were sepsis, COVID-19, immune thrombocytopenia, secondary myelofibrosis, pneumonia, acute kidney injury, agranulocytosis, hypertensive heart disease with heart failure, and blood transfusion reactions.Among readmitted patients, 55.7% had Medicare as the primary payer, 10.2% had Medicaid, 29.4% had private insurance, 1.7% were self-pay, and 0.2% had no charge or charity care status (p < 0.0001). Compared to Charlson category 1, readmitted patients were more often classified as Charlson 2 (35.8%) or 3 (64.2%) (p < 0.0001).Regarding hospital characteristics, 11.4% of readmissions occurred in small-bed hospitals, 17.6% in medium-sized hospitals, and 71.0% in large hospitals (p < 0.0001). Large metropolitan hospitals accounted for 67.2% of readmissions, small metropolitan for 29.6%, non-metro urban for 2.5%, and rural hospitals for 0.7% (p = 0.0317).Based on the multivariable Cox regression model, several factors were independently associated with 90-day readmission risk. Increasing age was linked to a lower likelihood of readmission (aHR = 0.988; 95% CI: 0.985–0.991; p < 0.001). Treatment at large hospitals was associated with higher risk (aHR = 1.16; 95% CI: 1.03–1.31; p = 0.018). HIV (aHR = 1.38; 95% CI: 1.12–1.71; p = 0.003) and gout (aHR = 1.17; 95% CI: 1.00–1.35; p = 0.045) were significant predictors of readmission. Conversely, neutropenia (aHR = 0.78; 95% CI: 0.70–0.86; p < 0.001) and sepsis (aHR = 0.79; 95% CI: 0.72–0.87; p < 0.001) during index admissions were associated with lower readmission risk, possibly reflecting higher acuity, longer stays, or mortality during the index hospitalization.Conclusion In this national analysis of DLBCL hospitalizations, 43% of patients were readmitted within 90 days, contributing to substantial healthcare burden. Readmission risk was influenced by age, hospital size, and comorbid conditions such as HIV, gout, neutropenia, and sepsis. These findings highlight key targets for improving care transitions and reducing avoidable readmissions.