The psoriatic inflammatory process is characterized by an overexpression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β compared with a relative deficiency of anti-inflammatory factors such as interleukin-10 and the interleukin-1 receptor antagonist (interleukin-1Ra). Gene polymorphisms that affect cytokine production may contribute to the disease-associated cytokine imbalance and influence susceptibility to psoriasis. Here, we investigated the relationship between polymorphisms in the genes encoding for tumor necrosis factor-α (G-238A, G-308A), interleukin-1β (C-511T, T+3953C), and interleukin-1Ra (intron 2), and cytokine production in peripheral blood mononuclear cells of healthy donors, and analyzed the distribution of these polymorphisms in patients with psoriasis vulgaris (n = 231) and healthy controls (n = 345). Carriage of tumor necrosis factor A-238 allele 2 (-238*A) was associated with increased production of tumor necrosis factor-α in response to lipopolysaccharide in vitro, and with early onset disease (< 40 y), especially in male patients with psoriasis [32% vs 7% in male controls; odds ratio = 6.78, 95% confidence interval = (3.18-15.15), padjusted = 2 × 10-7]. Carriage of the interleukin-1B-511*1 (-511*C) homozygous genotype was associated with increased production of interleukin-1Ra in response to lipopolysaccharide and interleukin-10, and with late onset psoriasis [≥ 40 y; 61% vs 44% in controls; odds ratio = 2.04, 95% confidence interval = (1.19-3.53), padjusted = 0.0419]. These findings indicate that gene polymorphisms associated with altered cytokine responses in vitro may modify age of onset of psoriasis. They also provide further evidence that patients with early and late onset psoriasis differ in their genetic background.