Background: Several risk factors for peptic ulcer disease (PUD) have been identified; however, the recurrence rates of PUD are still high even with standard ulcer treatments. A high cholesterol level has been proposed as a risk factor for PUD, but clinical evidence remains limited. Therefore, this database study investigated whether hyperlipidemia increases PUD risk and whether antihyperlipidemic drugs reduce this risk., Methods: A long-term cohort design was adopted, and Taiwan's National Health Insurance Research Database was used to enroll patients diagnosed as having hyperlipidemia between 2000 and 2016. Patients without hyperlipidemia were randomly matched based on variables such as age and gender to establish a comparison cohort at a 1:1 ratio. Another cohort study was conducted to determine whether antihyperlipidemic drugs or red yeast rice prescriptions (LipoCol Forte®) can reduce the incidence of PUD in patients with hyperlipidemia., Results: The overall incidence of PUD was 1.48 times higher in the hyperlipidemia cohort (203,235 patients) than in the nonhyperlipidemia cohort (adjusted hazard ratio, 1.48; 95% CI, 1.46-1.50; p < 0.001). Among the patients with hyperlipidemia, those who used antihyperlipidemic drugs with or without red yeast rice prescriptions exhibited a lower risk of developing PUD relative to those who did not use them; the adjusted hazard ratios were 0.33 (95% CI, 0.21-0.52) and 0.81 (95% CI, 0.78-0.84), respectively. When the cumulative exposure to antihyperlipidemic drugs and red yeast rice prescriptions increased, the risk of developing PUD showed a decreasing trend, which was statistically significant for antihyperlipidemic drugs but not for red yeast rice., Conclusion: Hyperlipidemia is associated with a higher risk of PUD, which can be reduced through antihyperlipidemic drugs with or without red yeast rice prescriptions administration., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)