Experimental studies showed a dose-dependent gastroprotective effect of statins on non-steroidal anti-inflammatory drug-induced endoscopic lesions, modulated by increasing endogenous nitric oxide and prostaglandin production.We investigated the influence of chronic treatment with statins on the occurrence of endoscopic lesions in patients referred for endoscopic evaluation, adjusted for the most important etiologic and risk factors for peptic ulcer disease and its complications.A consecutive series of 564 patients who underwent upper digestive endoscopy, stratified according to the severity of endoscopic lesions were recruited. Patients with statin therapy were included in the study group (n = 220), while patients without statins in the control group (n = 344). We correlate the influence of chronic statin therapy (at least 6 months) with factors including age up to 50 years, Helicobacter pylori infection, smoking and drinking habits, ulcer history, gastrotoxic drug consumption (low-dose aspirin [ASA], anticoagulants), and comorbidities.H pylori infection was more frequent in patients with mild/severe endoscopic lesions vs. no lesions, in both groups, but the difference was not statistically significant (P >.05). Male gender represented a risk factor (P <.01) for mild/severe endoscopic lesions only in the statin group. The estimated risk for developing mild/severe endoscopic lesions with ASA intake decreased from 6.26 to 3.40 (P <.01) when statin therapy was associated. Patients without statins and ischemic coronary artery disease (P <.01; odds ratio [OR] = 2.99; 95% confidence interval (CI):1.88-4.73), heart failure (P = .01; OR = 2.13; 95% CI:1.36-3.34), systemic atherosclerosis (P = .04; OR = 2.30; 95% CI:1.44-3.67) had a statistically significant increased risk for developing mild/severe endoscopic lesions in comparison with patients in the statin group. In multivariate regression analysis models, smoking (P <.01; OR = 2.69; 95% CI:1.73-4.16), ASA (P <.01; OR = 4.54; 95% CI:2.83-7.16), and coronary artery diseases (P = .01; OR = 1.80; 95% CI:1.15-2.82) were independent risk factors for mild/severe endoscopic lesions, while chronic statin therapy (P <.01; OR = 0.31; 95% CI:0.19-0.51) was associated with a protective effect in all models.The results of the present study support a certain protective role of chronic therapy with statins against endoscopic lesions, especially in ASA consumers or patients with cardiovascular diseases.