We searched a yeast genomic library for genes that conferred methylmercury resistance to yeast. Ymr258c was identified as a factor that conferred strong methylmercury resistance when overexpressed in budding yeast. Ymr258c is regarded as one of the F-box proteins, i.e., component factors of the Skp1/Cullin/F-box protein (SCF) complex that functions as a ubiquitin ligase in the ubiquitin-proteasome system. In this study, Ymr258c was demonstrated to function as an F-box protein to reduce methylmercury toxicity. The overexpression of Ymr258c might promote the ubiquitination of proteins that are involved in the enhancement of methylmercury toxicity, and thereby promote their degradation by proteasomes to reduce methylmercury toxicity.