Psoriasis, characterized by circumscribed, red, thickened plaques with an overlying silver-white scale, is a common T-cell-mediated chronic inflammatory skin disease. Although hydrogen sulfide (H(2)S) has been shown to be a signaling molecule with both pro- or anti-inflammatory effects, its relationship with psoriasis has not been elucidated. In the present study, 15 patients with chronic progressive psoriasis and 15 healthy volunteers were investigated. Serum H(2)S levels in psoriasis patients were significantly lower than those of healthy controls (16.69 ± 5.47 μM vs. 34.5 ± 6.39 μM). In contrast, serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) were significantly higher in psoriasis patients than healthy controls (22.88 ± 6.24 pg/ml vs. 12.07 ± 3.68 pg/ml; 61.47 ± 8.21 pg/ml vs. 31.54 ± 13.73 pg/ml; and 39.43 ± 8.56 pg/ml vs. 20.55 ± 6.45 pg/ml, respectively). The serum H(2)S levels negatively correlated with clinical disease severity. Furthermore, treatment of HaCaT human keratinocytes with TNF-α increased the levels of nitric oxide (NO), IL-6 and IL-8 (32.21 ± 5.71 μM vs. 3.22 ± 0.98 μM; 203.96 ± 13.16 pg/ml vs. 13.57 ± 3.75 pg/ml; and 301.24 ± 30.17 pg/ml vs. 29.06 ± 10.91 pg/ml, respectively) in the culture media. Exogenous H(2)S inhibited the TNF-α-mediated upregulation of NO, IL-6 and IL-8 in a dose-dependent manner. In addition, H(2)S inhibited TNF-α-mediated activation of p38, extracellular-signal-regulated kinase and nuclear factor kappa B. In conclusion, H(2)S may play a protective role in the pathogenesis of psoriasis. H(2)S-releasing agents may be promising therapeutics for psoriasis.