Proton pump inhibitors (PPI) are commonly used drugs. However, little is known about the association between PPI use and rosacea. This study aimed to investigate the association between PPI use and rosacea risk. Patients with prior PPI therapy, including 1067 rosacea cases and 4268 matched controls, were identified from the National Health Insurance Research Database in Taiwan. The cumulative defined daily dose (cDDD) was used to quantify the PPI use. Logistic regression was used for the analyses. After adjustment for potential confounders, PPI use with cDDD of more than 365 was significantly associated with an increased risk of rosacea (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.10–2.15). Rosacea risk was significantly associated with PPI use of cDDD of more than 365 in women (OR, 1.62; 95% CI, 1.08–2.46) but not in men. Stratified by PPI indications, risk of rosacea was significantly associated with PPI use of cDDD of more than 365 for peptic ulcer (OR, 1.58; 95% CI, 1.12–2.21). In conclusion, prolonged PPI use was associated with an increased risk of rosacea, particularly in women and patients with peptic ulcers.