Here, we identified HMG-CoA synthase 1 (HMGCS1), the upstream ketogenic enzyme of HMGCL, as an additional "synthetic lethal" partner of BRAF<sup>V600E</sup> Although HMGCS1 expression did not correlate with BRAF<sup>V600E</sup> mutation in human melanoma cells, HMGCS1 was selectively important for proliferation of BRAF<sup>V600E</sup>-positive melanoma and colon cancer cells but not control cells harboring active N/KRAS mutants, and stable knockdown of HMGCS1 only attenuated colony formation and tumor growth potential of BRAF<sup>V600E</sup> melanoma cells.