Objective: The aim of this study was to determine the characteristics of patients without Helicobacter pylori infection who were prescribed antacid medications (potassium-competitive acid blockers, proton pump inhibitors, and/or H<sub>2</sub> receptor antagonist) and had no upper gastrointestinal lesions detected by endoscopy. Methods: This cross-sectional study included the patients who underwent upper gastrointestinal endoscopy in our institution between August 2017 and July 2018. They were aged from 55 to 89 years, had no upper gastrointestinal lesions detected by endoscopy, and no H. pylori infection. Exclusion criteria comprised low-dose aspirin and/or nonsteroidal anti-inflammatory drugs. The subjects were allocated to middle-aged (55–69 years) and older age groups (70–89 years). The relationships between antacid medications and patient lifestyle and comorbidities were evaluated by multivariate analyses. Results: Of the 420 patients, 272 were in the middle-aged group and 148 patients in the older age group. Age was found to be a risk factor for antacid medications in both groups (p = 0.002, p = 0.007). No other lifestyle related factors were risk factors. As to comorbidities, hiatal hernia was positively associated with antacid medications in the middle-aged group (p = 0.002). Hypertension and Ca-blockers were positively associated with prescription of antacids in the older age group (p = 0.013); this association was not significant in the middle-aged group. Conclusions: Three lifestyle-related and/or comorbidity-associated factors known to exacerbate gastroesophageal reflux, namely, age, hiatus hernia, and Ca-blockers, were associated with prescription of antacid medications, even in patients without endoscopic reflux esophagitis.