Both the von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) pathway and microRNA (miRNA) regulation are important mechanisms underlying the development and progression of clear cell renal cell carcinoma (ccRCC). Here we demonstrate that VHL deficiency leads to downregulation of Dicer and, in turn, defects in the miRNA biogenesis machinery in ccRCCs. Dicer inhibited expression of HIF-2α, which was a direct target of Dicer-dependent miR-182-5p in VHL-deficient ccRCCs. Ectopic Dicer expression in VHL-deficient ccRCCs suppressed tumor growth and angiogenesis by inhibiting HIF-2α both in vitro and in vivo. Reduced Dicer mRNA levels served as an independent prognostic factor for poor survival in patients with VHL-deficient ccRCC. Our results indicate that downregulation of Dicer in VHL-deficient ccRCCs contributes to high levels of HIF-2α and a malignant phenotype, which suggests Dicer could be a useful therapeutic target for managing this disease.