Background: The additional benefits of certain frequently used chronic drugs such as statins or aspirin are investigated for their possible effect of influencing various types of cancer, including gastric cancer. The possible role of statins in the occurrence of pre-neoplastic gastric lesions has not been investigated. Aim: The study aims to determine the influence of chronic statin therapy on premalignant gastric lesions (glandular atrophy, intestinal metaplasia and dysplasia), adjusted with the most important aggressive environmental factors of the gastric mucosa (Helicobacter pylori [H. pylori] infection, low-dose aspirin [acetylsalicylic acid, ASA], biliary reflux, smoking, alcohol consumption). Method: The study included 566 patients with cardiovascular diseases who underwent an upper endoscopy: 222 patients with chronic statin therapy (atorvastatin 20–80 mg/day or rosuvastatin 5–20 mg/day for at least 6 months) and 344 patients without statin intake. A complete set of biopsies from the gastric antrum and corpus were routinely processed and examined, and demographical, clinical, and pathological variables were recorded. Results: Active H. pylori infection in gastric biopsies (p = 0.45), biliary reflux (p = 0.74), alcohol consumption (p = 0.43), or prior ulcer disease (p = 0.07; OR: 0.59; 95% CI: 0.33–1.04) were not associated with an increased risk for premalignant lesions, neither in the statin, nor the no-statin group. Smoking was associated with premalignant lesions in both groups (p = 0.01; OR: 2.24; 95% CI: 1.12–4.47; and p = 0.04; OR: 1.72; 95% CI:
1.01–2.94, respectively), while chronic use of ASA had no influence (p = 0.24, respective p = 0.35). In multivariate regression models, chronic treatment with statins had a protective effect (p = 0.006; OR: 0.59; 95% CI: 0.4–0.8), while smoking (p = 0.01; OR: 1.99; 95% CI: 1.17–3.39) and age >50 years (p <0.01, OR: 3.09; 95% CI: 1.84–5.21) were predictors for pre-neoplastic lesions. H. pylori infection, gender, alcohol consumption, biliary reflux, or prior ulcer disease were not associated with premalignant lesions (p >0.05). Conclusions: In the studied population, chronic statin treatment seems to be associated with a decreased risk for premalignant gastric lesions, while age over 50 years and smoking, regardless of gender or ASA consumption, remain the most important risk factors for premalignant gastric lesions.