The contribution of atypical PKC to angiotensin II (Ang II)-accelerated restenosis after endoluminal vascular injury was investigated using the rat carotid balloon injury model. Exposure of injured arteries to Ang II resulted in an extensive neointimal thickening (1.9 times) as compared to vehicle at day 14. Treatment with PKC antisense (AS), but not scrambled (SCR), oligonucleotides reduced neointimal formation observed in the presence or absence of Ang II. Examination of early events (2 days) following injury showed an increase in cellularity in the perivascular area of the artery wall that was transferred to the adventitia and media after exposure to Ang II, events blocked by PKC AS, but not SCR oligonucleotides. A positive correlation between medial cellularity at day 2 and extent of neointimal growth at day 14 was established. Immunohistochemical analysis showed that up-regulation of inflammatory markers after injury, as well as infiltration of ED1⁺ monocytes/macrophages from the perivascular area to the adventitia, were accelerated by Ang II. However, Ang II-stimulated medial increase in cellularity was proliferation-independent and these cells were MCP-1⁺/vimentin⁺, but ED1^-/VCAM^-. PKC is degraded after injury and inhibition of its neosynthesis in medial vascular smooth muscle cells (VSMC) or in infiltrating cells with PKC AS attenuated medial cellularity and expression of inflammation mediators without reversing dedifferentiation. Together, these data indicate that PKC plays a critical role in normal and Ang II-accelerated neointimal growth through a mechanism involving up-regulation of inflammatory mediators leading to cell infiltration in the media of the vascular wall.