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Abstract Comorbidity scores are important predictors of in-hospital mortality after traumatic spinal cord injury (tSCI), but the impact of specific pre-existing diseases is unknown. This retrospective cohort study aims at identifying relevant comorbidities and explores the influence of end-of-life decisions. In-hospital mortality of all patients admitted to the study center after acute tSCI from 2011 to 2017 was assessed. A conditional inference tree analysis including baseline data, injury characteristics, and Charlson Comorbidity Index items was used to identify crucial predictors. End-of-life decisions were recorded. Three-hundred-twenty-one patients were consecutively enrolled. The median length of stay was 95.7 days (IQR 56.8–156.0). During inpatient care, 20 patients (6.2%) died. These patients were older (median: 79.0 (IQR 74.7–83.2) vs. 55.5 (IQR 41.4–72.3) years) and had a higher Charlson Comorbidity Index score (median: 4.0 (IQR 1.75–5.50) vs. 0.0 (IQR 0.00–1.00)) compared to survivors. Pre-existing kidney or liver disease were identified as relevant predictors of in-hospital mortality. End-of-life decisions were observed in 14 (70.0%) cases. The identified impairment of kidney and liver, important for drug metabolism and elimination, points to the need of careful decisions on pharmaceutical treatment regimens after tSCI. Appropriate reporting of end-of-life decisions is required for upcoming studies.