Sulfate-reducing bacteria (SRB) are anaerobes readily found in oxic-anoxic interfaces. Multiple defense pathways against oxidative conditions were identified in these organisms and proposed to be differentially expressed under different concentrations of oxygen, contributing to their ability to survive oxic conditions. In this study, Desulfovibrio vulgaris Hildenborough cells were exposed to the highest concentration of oxygen that SRB are likely to encounter in natural habitats, and the global transcriptomic response was determined. Three hundred and seven genes were responsive, with cellular roles in energy metabolism, protein fate, cell envelope and regulatory functions, including multiple genes encoding heat shock proteins, peptidases and proteins with heat shock promoters. Of the oxygen reducing mechanisms of D. vulgaris only the periplasmic hydrogen-dependent mechanism was up-regulated, involving the [NiFeSe] hydrogenase, formate dehydrogenase(s) and the Hmc membrane complex. The oxidative defense response concentrated on damage repair by metal-free enzymes. These data, together with the down-regulation of the ferric uptake regulator operon, which restricts the availability of iron, and the lack of response of the peroxide-sensing regulator operon, suggest that a major effect of this oxygen stress is the inactivation and/or degradation of multiple metalloproteins present in D. vulgaris as a consequence of oxidative damage to their metal clusters.