PDR13 in Saccharomyces cerevisiae contributes to drug resistance via sequential activation of PDR1 and PDR5. In this study, we found that a PDR13 deletion mutant was hypersensitive to Cu(2+) compared to the wild-type counterpart. The Cu(2+) tolerance mechanism mediated by Pdr13 does not seem to involve Pdr1 or Pdr5, since mutants harboring a deletion of either the PDR1 or PDR5 gene did not show elevated Cu(2+) sensitivity. Instead, we found that the PDR13 null mutant could not express CUP1 or CRS5 metallothionein at wild-type levels when subjected to high Cu(2+) stress. These results suggest that Pdr13 contributes to high Cu(2+) tolerance of S. cerevisiae, at least in part, via a mechanism involving metallothionein expression.