Overexpression of antimicrobial peptides and proteins (AMPs) such as human β-defensin-2 (hBD2), LL37, and psoriasin has frequently been observed in lesional skin of psoriasis patients. We aimed to evaluate whether circulating AMP levels correlate with disease severity, and change under therapy with fumaric acid esters (FAE). We studied psoriasis patients who underwent systemic therapy using oral FAE (Fumaderm^®). An enzyme-linked immunosorbent assay for the detection of serum protein expression of hBD2, LL37, and psoriasin was performed at baseline and after 12-week therapy. After 12-week FAE treatment of 28 patients, the median PASI significantly (P < 0.0001) decreased from 27.1 to 12.5. In psoriasis patients, mean ± SD serum hBD2, psoriasin, and LL37 levels at baseline were 295.6 ± 93.5 pg/ml, 79.4 ± 32.7 ng/ml, and 106.3 ± 90 ng/ml, respectively, which were significantly increased when compared to healthy controls (110 ± 53.7 pg/ml, P ≤ 0.0001; 3.1 ± 0.7 ng/ml, P ≤ 0.0001; 3.8 ± 0.9 ng/ml, P = 0.0004, respectively). After 12-week FAE treatment, a significant increase of serum hBD2 (339.7 ± 74.3 pg/ml; P = 0.0046), psoriasin (106 ± 58.9 ng/ml; P = 0.0014), and LL37 (136.6 ± 115.1 ng/ml; P = 0.0035) was observed. Correlation studies did not reveal significant relationships between serum AMP levels and PASI (r < 0.1; P > 0.05). In contrast to AMP expression in psoriatic skin serum, AMP levels seem not to correlate with disease severity. Increased serum AMP protein levels in psoriasis resolution are an unexpected observation that needs to be investigated more in detail in future studies.