Staphylococcus aureus is known for its ability to cause chronic reoccurring infections in clinical settings. The organism’s ability to thrive despite antibiotic treatment has led to the severity of disease that is often exhibited with these infections. It has been hypothesized that energy-dependent persister formation leads to antibiotic tolerance in S. aureus. Persister cells are a dormant-like phenotypic variant of S. aureus that resemble cells growing in stationary phase. Previously, it was shown that a knockout in the tricarboxylic acid (TCA) cycle gene, fumC, which reduced intracellular ATP, led to an increase in the number of persisters. While persisters have been examined in relationship to antibiotic tolerance, it is currently unknown how persisters interact with the innate immune system. Considering a vast amount of chronic reoccurring infections in a clinical environment involve a biofilm, persisters were examined in a biofilm-associated catheter infection within a mouse. Following a 9 day infection, the fumC knockout exhibited increased survival within the tissue surrounding the catheter and within the heart compared to wild type S. aureus. Fluorescent activated cell sorting (FACS) analysis revealed similar recruitment of M1 and M2 macrophages, as well as neutrophils, suggesting there was not a difference in immunogenicity between the two strains. The fumC knockout exhibited increased survival compared to wild type S. aureus within a macrophage demonstrating persisters are better equipped to tolerate the innate immune system. These results indicate persisters are not only a problem with antibiotic treatment but are also better suited to survive the host’s immune system leading to increased survival within a host.