Proinflammatory genetic profiles, resulting from the combination of single nucleotide polymorphisms in genes encoding inflammatory molecules, may contribute to the development and progression of cardiovascular diseases. We evaluated the association between history of ischemic stroke and genetic profiles determined by the synergistic effects of polymorphisms in genes encoding prototypical inflammatory proteins. The study included 237 individuals with history of ischemic stroke and 223 age-matched and gender-matched controls. The polymorphisms of the C-reactive protein (CRP), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin (E-sel), and matrix metalloproteinase-3 (MMP-3) genes were studied. IL-6 GG, IL-6 GC, MCP-1 GG, ICAM-1 EE, E-sel AA, and MMP-3 5A5A genotypes were significantly and independently associated with stroke history. The odds of stroke increased with the number of high-risk genotypes: carrying 1 proinflammatory gene variant conferred a risk of 3.3 (1.6 to 6.9), whereas individuals concomitantly carrying 2 and 3 proinflammatory gene variants had adjusted odds ratios of 21.0 (7.6 to 57.5) and 50.3 (10.2 to 248.1), respectively. Proinflammatory genetic profiles are significantly more common in subjects with stroke history. Synergistic effects between proinflammatory genotypes might be potential markers for cerebrovascular diseases.