A role for the innate immune system in driving the autoimmune T cell cascade in psoriasis has been proposed. Toll-like receptors-(TLR)-2 and -4 play a role in inflammation, atherosclerosis, and their specific role in psoriasis remains unclear. To evaluate TLR2 and TLR4 gene expression levels in peripheral blood mononuclear cells from psoriatic patients. Changes in TLR2 / 4 gene expressions were evaluated using quantitative real-time reverse transcription polymerase chain reaction in peripheral blood mononuclear cells, from twenty-one patients with severe psoriasis, and analysed whether there was any correlation with cytokine plasma levels (T-helper 0-, T-helper 1-, T-helper 2- or regulatory T cells-type), or Calprotectin and with S100A8 and S100A9 gene expression levels. Eleven non-psoriatic healthy controls were analysed. A clear increase in TLR4 gene expression was observed (3.84 ± 0.93, n = 21) together with a moderate increase in TLR2 expression (1.522 ± 0.31, n = 21). Both TLR4 and TLR2 gene expressions were significantly augmented in psoriatic patients compared with controls (all P < 0.001). Correlations between TLR2 and S100A9 gene expressions (r = 0.5145, P = 0.0170, n = 21); and between TLR2 expression and plasma interleukin-2 (r = 0.5667, P = 0.0074); interleukin-4 (r = 0.4766, P = 0.0289), interleukin-10 (r = 0.4355, P = 0.0484) and interleukin-13 (r = 0.4603, P = 0.0358), were found. When patients with atheroma plaque were considered (n = 7), both TLR4 (3.47 ± 0.99, P = 0.0156) and TLR2 (1.63 ± 0.31, P = 0.0156) expressions were significantly increased vs. controls and correlated with plasma TNF-a (r = 0.8929, P = 0.0123, in both cases). Differential TLR4 / 2 gene expressions on psoriatic peripheral blood mononuclear cells and correlations with regulatory and / or proinflammatory cytokines and / or damage-associated molecular pattern molecule S100A9 emphasize innate immune response role in psoriasis.