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<i>Cryptococcus neoformans</i> is an encapsulated yeast pathogen that infects immunocompromised patients to cause fungal meningitis, resulting in hundreds of thousands of deaths each year. F-box protein Fbp1, the key component of the E3 ubiquitin ligase, plays a critical role in fungal development and virulence in fungal pathogens. In this study, we identified a potential substrate of Fbp1, the vacuolar morphogenesis protein Vam6-like protein Vlp1, and evaluated its role in virulence in <i>C. neoformans</i>. Deletion or overexpression of the <i>VLP1</i> gene results in abnormal capsule formation and melanin production of <i>C. neoformans</i>. Stress tolerance assay showed that the <i>vlp1</i>Δ mutant was sensitive to SDS and NaCl but not to CFW or Congo red, indicating that Vlp1 might regulate the cell membrane integrity in <i>C. neoformans</i>. Fungal virulence assay showed that Vlp1 was essential for the pathogenicity of <i>C. neoformans</i>, as <i>vlp1</i>Δ mutants are avirulent in the mouse systematic infection model of cryptococcosis. The progression of fungal infection revealed that the <i>vlp1</i>Δ mutants were gradually eliminated from the lungs of the mice after infection. Moreover, the <i>vlp1</i>Δ mutants showed a proliferation defect inside macrophages and a viability defect in the host complement system, which likely contributes to the virulence attenuation of the <i>vlp1</i>Δ mutants. In summary, our results revealed that the vacuolar morphogenesis protein Vam6-like protein Vlp1 is essential for the pathogenicity of <i>C. neoformans</i>.