OBJECTIVES: Hospital-acquired infections (HAIs) pose a significant risk to hospitalised patients. This study aimed to assess the relationship between medication use and the occurrence of HAIs. METHODS: This retrospective multicentre case -control study included 604 HAI cases reported across three hospitals in northwest China from January 2023 to July 2024. The control group consisted of 604 patients without HAIs from the same period and same hospitals. We performed multivariable log-binomial regression to assess the association between medication use and HAIs, adjusting for confounding variables. A trend chi-squared test was also used to evaluate if the risk of HAIs increased with longer medication durations. RESULTS: Univariate analysis revealed that the use of proton pump inhibitors (PPIs), antibiotics, glucocorticoids, and H2 receptor blockers significantly increased the risk of HAIs (P <
0.05. Multivariable log-binomial regression indicated that PPIs, glucocorticoids, and H2 receptor antagonists were associated with an elevated risk of HAIs, with relative risks (RRs) of 1.37 (95% CI: 1.19-1.57), 1.33 (95% CI: 1.10-1.62), and 1.84 (95% CI: 1.04-3.24), respectively. The duration of prolonged use of PPIs and glucocorticoids was significantly longer in the case group. CONCLUSIONS: Glucocorticoids, PPIs, and H2 receptor antagonists increase HAI risk, with prolonged use exacerbating this risk. The use of a single antibiotic for up to 10 days is not associated with HAI acquisition.