The aim of this study was to characterize the opening of the blood-brain barrier (BBB) in the primary stage of 50% total burn surface area in third degree scalded rabbits. Thirty healthy male New Zealand white rabbits were randomly assigned to 1, 2, 3 and 4 hours post scald groups and an untreated control were used to establish a 50% total burn surface area third degree scalded model. I-labeled bovine serum albumin was used as a tracer to identify the earliest time point of BBB opening after a severe scald. Dual source CT and magnetic resonance imaging were used to visualize cerebral changes in vivo. Samples taken from the bilateral frontal, temporal, posterior cortex, cerebellum, brain stem, and basal ganglia were examined by light microscopy and transmission electron microscopy. Transmission electron microscopy observations confirmed that BBB had begun to open at 2 hours post scald. Intracellular edema of basal lamina and gliocytes, and the breakdown and an indistinct appearance of the tight junction of vascular endotheliocytes were observed at 3 hours post scald. A marked increase of I-labeled bovine serum albumin intake was recorded at 3 hours post scald in all parts of the brain. Significantly reduced apparent diffusion coefficient values calculated from diffusion-weighted imaging were measured at 4 hours post scald within region of interests in all parts of the brain applied on apparent diffusion coefficient images. No significant alteration was seen in CT, diffusion-weighted imaging, T1 or T2 weighted images. Opening of the BBB had begun at 2 hours post scald; ie, before the occurrence of edema. The results of this study suggest that opening of the BBB might be a prerequisite for brain edema.