Immune complexes are potent inflammatory mediators in peripheral tissues. However, very few studies have examined the ability of immune complexes to induce inflammatory responses in the brain. Therefore, the objective of this study was to investigate the ability of immune complexes to induce an inflammatory response in the cerebral (pial) microvasculature, using either pre-formed immune complexes or the reverse passive Arthus (RPA) model to localize immune complexes to the pial microvasculature of mice. Application of pre-formed immune complexes immediately increased pial microvascular permeability, with a minimal change in leukocyte adhesion in pial post-capillary venules. In contrast, initiation of the RPA response in the pial microvasculature induced changes in cerebral microvascular permeability and increased leukocyte adhesion in pial post-capillary venules. In the RPA response, C3 deposition occurred in perivascular regions adjacent to sites of immune complex formation. Depletion of C3 abrogated RPA-induced microvascular permeability and leukocyte adhesion indicating that the complement pathway was critical for this response. Inhibition of leukocyte adhesion via CD18 blockade also reduced immune complex-induced microvascular permeability. However, this did not require ICAM-1 as blockade of ICAM-1 did not alter RPA-induced microvascular permeability and adhesion. These findings demonstrate that immune complexes are capable of rapidly inducing inflammatory responses in the cerebral microvasculature, with the complement pathway and leukocyte recruitment playing critical roles in microvascular dysfunction.