Cu,Zn superoxide dismutase (Sod1) is required for insusceptibility of Saccharomyces cerevisiae to oxytetracycline (OTC). Here we report that Sod1 is also required for insusceptibility to doxycycline (DOX). Furthermore, among a range of antioxidant and redox balance mutants, mac1 and ctr1 deletion strains exhibited marked sensitization to OTC and DOX. Certain mutants exhibited a slight sensitivity to methacycline and minocycline. Addition of copper suppressed antibiotic sensitivity. Thus, intracellular copper as well as superoxide dismutase can be critical for eukaryotic tolerance of several tetracycline antibiotics.