Introduction: Cardiovascular adverse effects of COX-2 inhibitors are well described. Nevertheless, no study explored the cutaneous and vascular adverse effects of COX-2 inhibitors, in particular the risk of skin ulcer. Objective: To identify and quantify the risk of skin ulcer (diabetic, pressure, venous or mixed) associated with COX-2 inhibitors in real world setting. Design: A population-based nested case control study was conducted from a representative sample of the French nationwide claims database for the 2012-2016 period. Setting: This database includes a 1/97th random sample of the population covered by the French healthcare insurance system. Participants: Cases were defined as patients who had consumed at least two boxes of wound dressing during one month between 2012 and 2016. The index date was the date of first period of reimbursement of wound dressing for skin ulcer. Up to four potential controls were selected for each case among subjects free from skin ulcers. Exposure: Exposure to COX-2 inhibitors was estimated using dispensing data. Cumulative exposure was expressed by Defined Daily Dose and anteriority of exposure by the Coverage End Date. Main Outcomes and Measures: Conditional logistic models were used to estimate adjusted odds ratios (aORs) and their 95% CIs. Cumulative exposure was considered using quartile as a categorical variable (0 to 14 days, 14 to 30 days, 30 to 90 days, ≥ 90 days and non-exposed). The anteriority of exposure was defined using a categorical variable (exposure during the period of 8 months before the index date: « recent users », the exposition overlap the index date: « current users » and exposure more than 8 months before the index date: « past users »). Results: We identified 2237 cases of diabetic foot ulcers and 8948 controls, 4225 cases of pressure ulcers and 16900 controls and 32246 cases of venous or mixed ulcers and 128902 controls, fulfilling the inclusion criteria. An increased risk of all types of ulcers was found for a cumulative exposure to COX-2 inhibitors exceeding 90 days with aOR= 1.35 (95% CI 1.03-1.77) for diabetic foot ulcer, aOR= 2.04 (95% CI 1.63-2.56) for pressure ulcers, aOR=1.89 (95% CI 1.71-2.11) for venous or mixed ulcers. Current exposure was associated with a higher risk of skin ulcer with aOR=1.63 (95% CI 1.06-2.49) for diabetic foot ulcer, aOR= 2.20 (95% CI 1.52-3.19) for pressure ulcers, aOR: 3.0 (95% CI 2.57-3.52) for vascular ulcers. Conclusions and Relevance: Our study suggests a risk of diabetic foot, venous or mixed and pressure ulcer associated with the use of COX-2 inhibitors. Given the observational nature of this study, we cannot exclude unmeasured and residual confounding.< Réduire