Purpose: The Berlin poly-trauma definition (BPD) has proven to be a valuable way of identifying patients with at least a 20% risk of mortality, by combining anatomical injury characteristics with the presence of physiological risk factors (PRFs). Severe isolated injuries (SII) are excluded from the BPD. This study describes the characteristics, resource use and outcomes of patients with SII according to their injured body region, and compares them with those included in the BPD. Methods: Data were extracted from the Dutch National Trauma Registry between 2015 and 2019. SII patients were defined as those with an injury with an Abbreviated Injury Scale (AIS) score ≥ 4 in one body region, with at most minor additional injuries (AIS ≤ 2). We performed an SII subgroup analysis per AIS region of injury. Multivariable linear and logistic regression models were used to calculate odds ratios (ORs) for SII subgroup patient outcomes, and resource needs. Results: A total of 10.344 SII patients were included; 47.8% were ICU admitted, and the overall mortality was 19.5%. The adjusted risk of death was highest for external (2.5, CI 1.9–3.2) and for head SII (2.0, CI 1.7–2.2). Patients with SII to the abdomen (2.3, CI 1.9–2.8) and thorax (1.8, CI 1.6–2.0) had a significantly higher risk of ICU admission. The highest adjusted risk of disability was recorded for spine injuries (10.3, CI 8.3–12.8). The presence of ≥ 1 PRFs was associated with higher mortality rates compared to their poly-trauma counterparts, displaying rates of at least 15% for thoracic, 17% for spine, 22% for head and 49% for external SII. Conclusion: A severe isolated injury is a high-risk entity and should be recognized and treated as such. The addition of PRFs to the isolated anatomical injury criteria contributes to the identification of patients with SII at risk of worse outcomes.