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The mechanistic relationship between the sexually dimorphic neuroimmune system and the sex-specific outcomes of a pubertal immune challenge is unclear. Therefore, we examined sex differences in the progression of cytotoxic microglial responses and blood-brain barrier (BBB) disruption to a peripubertal lipopolysaccharide (LPS) treatment in brain regions relevant to stress responses and cognitive function. Six-week-old (i.e., stress-sensitive pubertal period) male and female CD-1 mice were treated with LPS (1.5 ​mg/kg body weight, ip ) or 0.9% saline (LPS-matched volume, ip ). Sex and treatment differences in microglial (Iba1 + ) and apoptotic neuronal (caspase-3 + /NeuN + ) and non-neuronal (caspase-3 + /NeuN − ) expression were examined in the hippocampus, medial prefrontal cortex (mPFC), and paraventricular nucleus 24 ​h (sickness), one week (symptomatic recovery) and four weeks (early adulthood) post-treatment ( n ​= ​8/group). Microglial morphology was quantified with fractal analyses. Group differences in BBB permeability to 14 C-sucrose were examined 24 ​h (whole-brain, hippocampus, prefrontal cortex, hypothalamus, and cerebellum) and one week (whole-brain) post-treatment. The acute effects of pubertal LPS were specific to females (i.e., global BBB disruption, altered microglial expression and morphology in the mPFC and hippocampus, increased hippocampal apoptosis). The residual effects of pubertal LPS-induced sickness observed in microglia persisted into adulthood in a sex- and region-specific manner. In addition to highlighting these sex-specific responses of the pubertal neuroimmune system, we report baseline region-specific sex differences in microglia spanning puberty through adulthood. We propose that these sex differences in neuroimmune-neurovascular interactions during the stress-sensitive pubertal period create sex biases in stress-related disorders of brain and behaviour.