BACKGROUND: Studies of neurologic outcomes have found conflicting results regarding differences between patients with substance-related cardiac arrests (SRCA) and non-SRCA. We investigate the effects of SRCA on severe cerebral edema development, a neuroimaging intermediate endpoint for neurologic injury. METHODS: 327 out-of-hospital comatose cardiac arrest patients were retrospectively analyzed. Demographics and baseline clinical characteristics were examined. SRCA categorization was based on admission toxicology screens. Severe cerebral edema classification was based on radiology reports. Poor clinical outcomes were defined as discharge Cerebral Performance Category scores>3. RESULTS: SRCA patients (N=86) were younger (P<0.001), and more likely to have non-shockable rhythms (P<0.001), be unwitnessed (P<0.001), lower Glasgow Coma Scale scores (P<0.001), absent brainstem reflexes (P<0.05) and develop severe cerebral edema (P<0.001) than non-SRCA patients (N=241). Multivariable analyses found younger age (P<0.001), female sex (P=0.008), non-shockable rhythm (P=0.01) and SRCA (P=0.05) to be predictors of severe cerebral edema development. Older age (P<0.001), non-shockable rhythm (P=0.02), severe cerebral edema (P<0.001), and absent pupillary light reflexes (P=0.004) were predictors of poor outcomes. SRCA patients had higher proportion of brain death (P<0.001) compared to non-SRCA deaths. CONCLUSIONS: SRCA results in higher rates of severe cerebral edema development and brain death. The absence of statistically significant differences in discharge outcomes or survival between SRCA and non-SRCA patients may be related to the higher rate of withdrawal of life-sustaining treatment (WLST) in the non-SRCA group. Future neuroprognostic studies may opt to include neuroimaging markers as intermediate measures of neurologic injury which are not influenced by WLST decisions.