Methotrexate (MTX) is a well-known and widely used treatment for psoriatic arthritis (PsA) and psoriasis (PsO). However, sex-differences in treatment of MTX has hardly been studied. Therefore, this study aimed to analyze how treatment effects of MTX differ between females and males. To do this, we use clinical data from patients with PsO and/or PsA treated with MTX across multiple hospitals in the Netherlands. We found that females with PsA, whereas males with PsO, tended to stop their MTX treatment earlier. Additionally, the disease activity was higher in females with PsA, and males with PsO, at the time of stopping MTX treatment. While the MTX dose was comparable between females and males, patients with PsA generally received a higher dose than patients with PsO. In conclusion, the effects of MTX differed not only between sexes but also between PsA and PsO. This highlights the importance of considering both a patient’s sex and type of disease when optimizing MTX treatment.