Given the inherent heterogeneity of the septic patient population and possible comorbid conditions, it is not surprising that the influence of gender on incidence and outcomes are still unclear. The goal of this study was to use a clinically relevant murine model of sepsis, cecal ligation and puncture (CLP) in CD1 mice, with and without uniphrectomy as a comorbid condition to investigate possible gender differences in renal mitochondrial function and dynamics. High resolution respirometry on fresh kidney biopsies was used to measure renal respiratory complex activities. At 18h post-CLP with nephrectomy male mice showed significant reductions in complex I, II, and III activities, while females were less effected; only complex I was significantly reduced from sham mice. Taken together, our studies revealed, for the first time, gender differences in mitochondrial respiratory activity even in the absence of sepsis. We also examined expression of key mitochondrial fission and fusion proteins. In both genders and in both CLP models, protein expression of the primary fission protein, DRP1 was significantly decreased. No changes were observed in female mice in either CLP model; whereas, male mice demonstrated a slight reduction in MFN1 and the short form of OPA1 after CLP, and modest increase in MFN2 with CLP plus nephrectomy. In both genders CLP with nephrectomy produced a greater increase in serum blood urea nitrogen, a biomarker of renal injury, than without nephrectomy. However, CLP with nephrectomy produced significantly lower 96-hour survival in females. Our results suggest that the CLP nephrectomy comorbid model of sepsis may be an appropriate model to study gender differences a select group of predisposed individuals.