<p>Preclinical studies indicate that volatile anesthetics such as sevoflurane induce neuroinflammation and oxidative stress—mechanisms implicated in the pathophysiology of depression—whereas propofol exhibits neuroprotective properties. However, whether these pharmacological differences translate into distinct long-term psychiatric outcomes in humans remains unclear. We conducted a multinational propensity score–matched cohort study using the TriNetX Global Federated Network (2005–2024) to determine whether sevoflurane anesthesia is associated with a higher risk of long-term depression compared with propofol. To isolate the effect of anesthetic choice, we applied a new-user design with a one-year latency washout, excluding patients with preexisting depression or antidepressant use. The primary outcome was new-onset depression diagnosed more than one year after anesthesia. The matched cohort included 37,936 patients balanced across more than 100 covariates. Sevoflurane exposure was associated with a higher risk of new-onset depression compared with propofol (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.41–1.61). The association remained consistent across severity strata (aHR, 1.51 for moderate-to-severe depression) and surgical subgroups. Notably, we observed a graded dose-response relationship, where repeated sevoflurane exposures conferred progressively higher risk (aHR, 1.75 for ≥2 exposures), consistent with a biologic gradient. In this large multinational cohort, sevoflurane use was associated with a higher long-term risk of incident depression compared with propofol. These findings align with preclinical evidence of anesthetic-related neuroinflammatory mechanisms and indicate that anesthetic selection may have implications for long-term neuropsychiatric risk. Further mechanistic and prospective studies are warranted.</p>