Our aim was to determine whether the HLA-Cw6 and late-cornified envelope (LCE) deletion polymorphisms were related to disease improvement among psoriasis patients treated with anti-tumor necrosis factor (TNF) antibodies. The study included a total of 116 patients. Positive response (68%) was defined as a reduction of at least 75% of the Psoriasis Area and Severity Index (PASI) after 24 weeks of starting the anti-TNF therapy. We found a trend toward a better response among Cw6-positive patients. The frequency of patients who did not reach the PASI75 was higher among the LCE-DD patients (P=0.028; odds ratio=2.45, 95% confidence interval=1.09-5.52). Patients who were Cw6-positive and LCE-I carriers (ID/II) were significantly more likely to reach PASI75 than those who were Cw6-negative and LCE-DD (P=0.034; odds ratio=3.14, 95% confidence interval=1.07-9.24). In conclusion, we found an interaction between the HLA-Cw6 and LCE genotypes on disease improvement among psoriatic patients treated with anti-TNFs.