Introduction: Stroke is a sexually dimorphic disease. There is growing evidence that there are sex differences in the response to drugs, both in experimental and in clinical studies. Increase in BBB permeability occurs after stroke, but little is known if BBB disruption and permeability differs in males and females. In our ongoing studies with Inter-alpha Inhibitor Protein (IAIP), we found that although IAIP is significantly efficacious in both sexes, it is more effective in males. Therefore, here we tested if the sex-specific differences in efficacy of IAIP is due to BBB permeability. Methods: Aged male and female mice (18-20 months; C57BL/6), were subjected to right middle cerebral artery occlusion (MCAO-60min) and randomly assigned to a vehicle/IAIP (30mg/kg) group. Infarcts were quantified at 7-days after stroke. Transport of IAIP across the BBB in vivo was directly investigated using 131 I-IAIP and 125 I-albumin (n=4/gp) at 6h & 24h after injection; Radioactivity was determined by a gamma counter. Brain and tissue uptake of 131 I-IAIP was determined by comparing to 125 I-albumin. Results: Aged males receiving IAIP had significantly reduced infarcts compared to vehicle treated mice in cortex (p=0.01), striatum (p=0.01) and in total hemispheric infarct (p=0.018) (n=8-10/grp). Female mice treated with IAIP also had a significant reduction in total infarct (p=0.04), but not in cortex or striatum. IAIP treated males had significantly lower mortality (p<0.05), but this was not seen in females. IAIP and albumin remained in the brain vascular space six hours after stroke in both sexes. However, at 24h, the brain distribution of 131 I-IAIP and 125 I-albumin in aged males was significantly higher than in shams, confirming brain entry. However, uptake of IAIP was only seen in males (P<0.05) and not in females. Conclusions: Our data demonstrates that 1) IAIP treatment is neuroprotective in both sexes, but more efficacious in males and 2) IAIP do not significantly cross the BBB early after stroke/reperfusion (6h), but crosses in a disruption-dependent manner at 24h, but only in males. This may be one explanation for the more robust neuroprotective effects seen in aged males vs. females. These studies may have far-reaching implications for other drug development strategies.