The female genital mucosa expresses the hormone-dependent type I interferon (IFN), IFN-epsilon (IFN-ε), which protects against chlamydia and herpes infection. Surprisingly, we found that IFN-ε knockout (Ifnε) mice and type I IFN receptor knockout (Ifnar1) mice exhibited enhanced clearance of Neisseria gonorrhoeae (Ng). This result was phenocopied using blocking anti-IFNAR monoclonal antibody (mAb). Ng colonization of the Ifnε urogenital tract was restored by exogenous recombinant IFN-ε or IFN-β. Clearance of Ng in anti-IFNAR-treated mice required the expression of the cathelicidin mCRAMP. Ng deploys a unique mechanism to evade cathelicidins and other innate defenses by sialylating its lipooligosaccharide (LOS) using host-derived cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac or CMP-sialic acid). Ifnε mice expressed reduced levels of CMP-sialic acid synthetase mRNA in genital tissues. Accordingly, Ng recovered from IFN-deficient mice were hyposialylated. In conclusion, Ng exploits type I IFNs to obtain CMP-sialic acid for LOS sialylation, resulting in innate immune evasion and enhanced colonization.