Cardiac arrest is often associated with poor neurologic outcome since therapeutic options are limited. We tested the hypothesis that overexpression of CuZn superoxide dismutase (SOD+/-) is neuroprotective in a new murine model of cardiac arrest and cardiopulmonary resuscitation (CPR). Second, we investigated if female and male mice sustain similar injury and if sex-specific outcomes are altered by SOD overexpression. Neuronal injury was quantified 3 days after 8 mins of KCl-induced cardiac arrest by calculating the percentage of ischemic neurons for caudoputamen and hippocampal CA1 region. In rostral caudoputamen, less neuronal cell loss was found for SOD+/- mice (31%+/-22%) when compared with wild-type (WT) mice (47%+/-31%, P<0.05). Superoxide dismutase overexpression did not reduce injury in the caudal caudoputamen. No sex-linked protection was evident in either genotype in the caudoputamen. Female WT mice had less CA1 injury than male WT mice (26%+/-31% versus 54%+/-30%, P<0.05), whereas no sex difference was found in SOD+/- mice (female: 42%+/-29%; male: 37%+/-37%). Comparison of hippocampal injury between genotypes revealed no differences for either males or females. In conclusion, SOD1 overexpression and female sex were associated with significant neuroprotection in this murine cardiac arrest model. However, no additive neuroprotection was observed, and these beneficial effects were restricted to specific brain regions.