Background: Tumor lysis syndrome (TLS) is a well-known potentially fatal complication of chemotherapy and an oncologic emergency. It is most prevalent in hematologic malignancies, but there are case reports and clinical series of occurrence after the treatment of solid tumors. Hospital readmissions are indicators of quality of care and cost control. We aim to look at the prevalence of readmissions after an initial episode of TLS in patients with solid malignancies and their financial burden on the United States healthcare system. Methods: We conducted a retrospective analysis of the 2017 National Readmission Database (NRD) of adult patients readmitted within 30 days after an initial “index” admission of TLS (ICD10 code E88.3) with a concomitant diagnosis of solid malignancy. We aimed to identify the 30-day readmission rate, mortality, healthcare-related utilization resources, and independent predictors of readmission by performing a COX regression analysis. Results: A total of 874 patients with solid tumors were admitted with TLS in 2017. The 30-day readmission rate was 20.4%. The main causes for readmission were sepsis, recurrent malignant lesions, metastasis to CNS, bleeding, acute kidney failure (AKI). Compared to initial admissions, readmitted patients were less likely to have acute kidney failure (AKI) (64.6% vs 30.8%; P < 0.01), less likely to require mechanical ventilation (17.9% vs 5.7%; P < 0.01), less likely to suffer shock (7.3% vs 2.3%; P = 0.03) and ileus (4.8% vs 0.7%; P = 0.04). Readmission was associated with higher in-hospital mortality rate (0.1% vs. 1.5%; P < 0.01), more likely to have private insurance (29.9% vs 36.1%; P < 0.01), and more likely to be discharged home (26.2% vs 36.8%; P < 0.01). The total health care in-hospital economic burden of readmission was $14.9 million in total charges to patients and $4 million in total costs for hospitals. Independent predictors of readmission were prolonged length of stay (during index admission), tobacco abuse, VTE, thrombocytopenia, and admission to an urban hospital. We identified the following preventive factors for readmission: radiation therapy, admission to a smaller hospital, total parenteral nutrition during the index admission and a primary gynecologic malignancy. Conclusions: Readmissions after TLS in patients with solid malignancy are associated with a higher in-hospital mortality rate and pose an increased health care burden. We identified risk factors that, if targeted, could lead to reducing readmissions, health care burden, and patient morbidity.