A case-control study was performed to assess the serum levels of TNF-α, IL-12/23p40, and IL-17 in patients with plaque psoriasis, compare them with healthy controls, and correlate them with disease severity, as represented by Psoriasis Area Severity Index (PASI). 32 consecutively selected, untreated patients with active, chronic plaque psoriasis were recruited and compared to 32 age- and sex-matched healthy controls. Serum cytokine levels were determined by solid phase sandwich enzyme linked immunosorbent assay (R&D Systems Europe, Ltd.). The mean serum levels of TNF-α were significantly higher in psoriatic patients compared to those of controls (Mann-Whitney U test; P = 0.000). However, the median serum levels of neither IL-12/23p40 nor IL-17 differ significantly between the 2 groups (Mann-Whitney U test; P = 0.968 and P = 0.311, resp.). No significant correlations were found between PASI and any of the cytokine serum levels (Spearman's rank test; P > 0.05). Despite the well-evidenced therapeutic efficacy of biologic agents targeting TNF-α, IL-12/23p40, and IL-17, serum levels of TNF-α, IL-12/23p40, and IL-17 do not seem to correlate with the severity of psoriatic skin disease in untreated patients, as represented by PASI. Further investigation may add more data on the pathogenetic cascade of psoriasis.