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There is a lack of real practice studies comparing ustekinumab and ixekizumab effectiveness and safety. The main aim of this study was to compare the effectiveness and safety of both drugs used to treat moderate‐to‐severe psoriasis patients over 52 weeks. The secondary objective was to identify which clinical variables could have an impact on its effectiveness. A retrospective observational study was carried out, comparing the first 28 patients treated with ustekinumab after its commercialization was compared to the first 35 patients treated with ixekizumab. Although a higher level of skin clearance was achieved with ixekizumab with a PASI 90 and 100 response of 54.3% and 40% compared to 42.9% and 25% for ustekinumab, these differences were not statistically significant. Ixekizumab achieved a higher PASI 90 response in those patients with BMI > 27 (slightly overweight), which was statistically significant (P = .024). Ustekinumab had a greater survival at 52 weeks than ixekizumab, with a trend towards statistical significance (P = .052). Ixekizumab achieved higher skin clearance rates (PASI 90 and 100 response) than ustekinumab, with no statistically significant differences. However, ixekizumab should be specially considered in overweight patients.