Epidermal necrolysis is a severe cutaneous adverse reaction in which severe systemic inflammation results in extensive epithelial keratinocyte necrosis. The most commonly used prognostic score in epidermal necrolysis, the Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN), was recently found to overestimate mortality in contemporary cohorts. Identification of independent prognostic markers may help to stratify risk more accurately. This study evaluates the association between novel inflammatory markers and in-hospital mortality in patients with epidermal necrolysis to study the incremental prognostic value of these markers in combination with SCORTEN. A retrospective cohort study was conducted over a 17-year period from 2003 to 2019. Patients were enrolled from Singapore General Hospital, the national referral center for epidermal necrolysis. A total of 196 patients with epidermal necrolysis were recruited, 4 (2%) of whom were excluded owing to incomplete data. The main outcome assessed was the in-hospital mortality rate. Discrimination and calibration of risk scores were assessed using the area under the receiver operating characteristic curve (AUC) and calibration plot, respectively. Evaluation of the incremental prognostic value of these markers was done by comparing the AUC between the old and new risk score, and the use of net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Among 192 total patients (median [IQR] age 56 [42-70] years; 114 [59.4%] women), there were 43 (22.4%) who did not survive to discharge. Of the novel inflammatory markers, only red cell distribution width to hemoglobin ratio was significant in predicting in-hospital mortality (odds ratio [OR] 3.55; 95% CI, 1.76-7.16; P < .001) after adjusting for SCORTEN. The RDW/Hb as applied in 4 risk groups showed similar discrimination to SCORTEN (AUC [95% CI]: RDW/Hb in 4 groups, 0.76 [0.69-0.84], vs SCORTEN, 0.78 [0.70-0.85], P = .89). When RDW/Hb was added to SCORTEN, the composite score Re-SCORTEN showed significantly better discrimination than SCORTEN alone (AUC [95% CI]: Re-SCORTEN, 0.83 [0.77-0.89], vs SCORTEN, 0.78 [0.70-0.85], P = .02). The overall NRI was 0.94 (95% CI, 0.68-1.20), P < .001. The IDI was 0.06 (95% CI 0.03-0.08), P < .001. Re-SCORTEN showed good calibration based on the calibration plot. In this cohort of patients, RDW/Hb, an inexpensive and readily available marker, showed similar predictive accuracy with SCORTEN. Furthermore, when used in combination with SCORTEN, it also helped augment prognostic ability.