Analysis of 35,610 matched patients with hyperlipidemia revealed PCSK9 inhibitors reduced depression risk by 26% compared to statins (HR 0.74), with 5-year incidence rates of 5.84% versus 7.91% respectively. The protective effect was specific to major depressive disorder, requiring treatment of 46 patients to prevent one case of depression over five years. This finding challenges assumptions about neuropsychiatric effects of cholesterol medications and suggests mechanistic differences between drug classes. While statins have long been scrutinized for potential mood effects, PCSK9 inhibitors appear to offer cardiovascular protection without the same psychiatric burden. The protective association remained consistent across different statin intensities and patient subgroups, strengthening the signal. However, this preprint awaits peer review, and the observational design cannot establish causation definitively. The mechanism remains unclear—whether through different cholesterol-lowering pathways, reduced inflammation, or other biological processes. Given depression's impact on cardiovascular outcomes, this represents a potentially significant clinical consideration in lipid management decisions, though confirmation through randomized trials is essential.