Deubiquitinating enzymes that influence the methylmercury susceptibility of yeast cells were investigated. Deficiency of Ubp2, Ubp4, Ubp 6, or Ubp14 conferred methylmercury resistance on cells, while deficiency of Ubp7, Ubp13, or Ubp15 conferred high methylmercury susceptibility. Of these enzymes, deficiency of Ubp4 and Ubp6 was associated with particularly high methylmercury resistance. Yeast cells treated with a proteasome inhibitor showed methylmercury resistance due to Ubp4 deficiency, but not due to Ubp6 deficiency. Thus, the enhanced methylmercury toxicity associated with Ubp6 expression requires proteasomal activity, suggesting that Ubp4 and Ubp6 contribute to enhanced methylmercury toxicity through different mechanisms.