Disordered immune responses and cholesterol metabolism have been implicated in age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals. SULT2B1, the key enzyme of sterol sulfonation, plays important roles in inflammation and cholesterol metabolism. However, the role and underlying mechanism of SULT2B1 in AMD have not been investigated thus far. Here, we report that SULT2B1 is specifically expressed in macrophages in choroidal neovascularization lesions.Sutl2b1deficiency significantly reduced leakage areas and inhibited pathological angiogenesis by inhibiting M2 macrophage activation in vivo and in vitro. Mechanistically, loss ofSult2b1activated LXRs and subsequently increased ABCA1 and ABCG1 (ABCA1/G1)-mediated cholesterol efflux from M2 macrophages. LXR inhibition (GSK2033 treatment) inSult2b1−/−macrophages reversed M2 polarization and decreased intracellular cholesterol capacity to promote pathological angiogenesis. In contrast to SULT2B1, STS, an enzyme of sterol desulfonation, protected against choroidal neovascularization development by activating LXR–ABCA1/G1 signalling to block M2 polarization. Collectively, these data reveal a cholesterol metabolism axis related to macrophage polarization in neovascular AMD.