PurposePsoriasis (PsO), a chronic inflammatory skin disorder affecting a substantial proportion of populations globally, often necessitates systemic treatment including biologics. This 14‐year cohort study, based on Danish national register data, aimed to investigate the enduring safety profile of ustekinumab compared to other systemic psoriasis treatments.MethodsUsing comprehensive Danish national register data, this study scrutinized patients diagnosed with psoriasis or psoriatic arthritis (PsA) who received ustekinumab. The treatment group comparators were non‐biological systemic treatment (non‐biologic), tumor necrosis factor α inhibitor medicine groups (TNF‐α), interleukin (IL)‐17 inhibitors (IL‐17), and IL‐23 inhibitors (IL‐23). The study periods for comparisons were 2009–2022 for non‐biologic and TNF‐α, 2015–2022 for IL‐17, and 2018–2022 for IL‐23. Outcomes were malignancies, cardiovascular events, serious infections, and serious hypersensitivity reactions. Cox proportional hazards regression models were employed to analyze two estimands: a standard intention‐to‐treat (ITT) estimand and a continuous‐index‐treatment (CIT) estimand, which considered switch and re‐initiation of treatments within individuals.ResultsUsers of ustekinumab were found to be younger on average, with an average age of 45.1 years compared to 51.6, 47.2, 49.0, and 48.4 years in the non‐biologic, TNF‐α, IL‐17, and IL‐23 groups, respectively. Also, 57.3% of the ustekinumab users were male, compared to 46.7%, 48.9%, 50.9%, and 58.3% for the non‐biologic, TNF‐α, IL‐17, and IL‐23 groups, respectively. Although the hazard ratio estimates varied across comparators, ustekinumab was found to be safe: regardless of PsA status, no discernible safety signals in terms of malignancy, MACE, severe infections, or severe hypersensitivity reactions were observed for ustekinumab when compared to the treatment comparators.ConclusionsThe present study corroborated the enduring safety of ustekinumab in the context of PsO treatment.