Background: Midline catheters have been considered a preferred alternative to peripheral intravenous catheters and central venous catheters. However, little is known about the safety of infusing irritants through midline catheters. We aimed to evaluate safety outcomes after the administration of irritants through midline catheters. Methods: This was a retrospective observational cohort study that included 1613 patients who had a midline catheter from April 2020 to December 2023. We used descriptive statistics and inferential statistics to characterize and compare the groups and conducted multivariable regression analysis adjusted for potential confounders. Subgroup analyses (with tests for interaction) were used. A 1:1 propensity score matching analysis was performed to repeat the analysis that achieved stringent control for confounders. Sensitivity analysis was conducted to test the stability of the results. Results: 1184 patients received irritants through midline catheters and 429 patients did not receive irritants. There were no significant differences in catheter-related complications between the groups (before matching: 9.9% vs 6.8%, p = 0.062; after matching: 9.9% vs 6.6%, p = 0.105). The multivariate analysis revealed that the platelet count, the catheter duration, and the vein selection were significant independent risk factors associated with catheter-related complications. Subgroup analyses indicated that there were no significant interactions. The results of the sensitivity analysis were robust. Conclusions: We found no significant association between the administration of irritants through midline catheters and catheter-related complications. However, the drug indications for midline catheters need to be further confirmed by well-conducted randomized clinical trials with large cohorts of patients.