Long-term acid suppression with proton pump inhibitors (PPI) leads to hypochlorhydria and facilitates the growth of bacterial flora in the small intestine. Novel acid-suppressants called potassium-competitive acid blockers (P-CABs) seem to be superior to PPIs. However, data on the risk of small intestinal bacterial overgrowth (SIBO) in patients taking P-CABs are limited. We retrospectively analyzed a consecutive series of patients with long-term acid-suppressant (PPIs or P-CABs) use for gastroesophageal reflux disease or nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. All of them underwent endoscopic examinations and testing and took PPIs or P-CABs for at least 3 months. Glucose hydrogen breath tests (GBT) were performed to check for SIBO, and newly developed SIBO-related symptoms including bloating, postprandial discomfort, diarrheas, and constipation, were evaluated. A total of 142 patients were enrolled. Six patients were excluded due to equivocal infection results. The frequency of positive GBTs was 31.7% (25/79) for PPI and 22.8% (13/57) for P-CAB use (=0.15). Regarding GBT positivity, age-related factor was found to be significant in multivariate analysis (=0.02). The results of multivariate analysis in cases of SIBO-related symptoms showed that GBT positivity and PPI use were significant ( < 0.01). Long-term use of gastric acid suppressants resulted in positive GBT in approximately 30% of patients, and the risk was particularly high in elderly patients. The occurrence of SIBO-related symptoms was significant in long-term use of PPIs and in patients with positive GBT.