Rationale: The extent, timing, and significance of mitochondrial injury and recovery in bacterial sepsis are poorly characterized, although oxidative and nitrosative mitochondrial damage have been implicated in the development of organ failure. Objectives: To define the relationships between mitochondrial biogenesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis. Methods: We developed a murine model of fibrin clot peritonitis using Staphylococcus aureus. The model yielded dose-dependent decreases in survival and resting energy expenditure allowing us to study recovery from sublethal sepsis. Measurements and Main Results: Peritonitis caused by 10⁶ CFU S. aureus induced a low TNF- state and minimal hepatic cell death, but activated the prosurvival ABC kinases sequentially over three days. Basal metabolism by indirect calorimetry was depressed due to selective mitochondrial oxidative stress and subsequent loss of mtDNA copy number. During recovery, mitochondrial biogenesis was strongly activated by regulated expression of the requisite nuclear respiratory factors (NRF-1 and -2) and the co-activator PGC-1, as well as repression of the biogenesis suppressor, RIP140. Biogenesis reconstituted mtDNA copy number and transcription, and restored basal metabolism without significant hepatocellular proliferation. These events dramatically increased hepatic mitochondrial density in transgenic mice expressing mitochondrially-targeted green fluorescent protein. Conclusions: This is the first demonstration that mitochondrial biogenesis restores oxidative metabolism in bacterial sepsis and is therefore an early and important prosurvival factor.