AbstractHydrocephalus is a disorder caused by excess fluid accumulation in the brain and results in brain damage with consequent cognitive and physical problems. This condition has no cure; the only treatment is brain surgery. Experimental data indicate that P‐glycoprotein (P‐gp) plays a crucial role in the pathogenesis of hydrocephalus due to its function in clearing macromolecules from the brain. Numerous medications frequently used are classified as P‐gp inducers or inhibitors, and comprehending their effects may aid in attaining improved patient outcomes. Therefore, in this single‐center retrospective study, we examined the risk of the need for ventriculoperitoneal shunt placement over 10 years among 4588 adult patients with hydrocephalus not exposed to any P‐gp inhibitors/inducers or exclusively exposed to either P‐gp inhibitors or inducers. Our analysis shows that patients exposed to P‐gp inhibitors had a 3.2 times higher risk of requiring ventriculoperitoneal shunt surgery (P < .0001). In contrast, the relative risk was not significantly affected (P = .07) among those exposed to P‐gp inducers. Our findings indicate the need for caution when prescribing P‐gp inhibitors to patients with hydrocephalus. Additional studies using larger cohorts are required to confirm whether P‐gp inducers in patients with hydrocephalus can mitigate the risk of ventriculoperitoneal shunt.