Abstract Staphylococcus aureus bacteremia is a potentially lethal infection particularly when involving methicillin-resistant S. aureus (MRSA). Contrary to MRSA bacteremia that resolves on its own (RB), persistent MRSA bacteremia (PB) happens when the infection persists after receiving antibiotic therapy. Host immune responses in PB vs. RB are poorly understood. Our goal was to identify proteomic, epigenetic, and transcriptomic features associated with PB and RB clinical outcomes. We examined the whole-blood transcriptomes of propensity score matched PB (n = 28) and RB (n = 30) patients. Gene expression (GE) modules were analysed by weighted gene co-expression network analysis (WGCNA) and quantified by module eigengene analysis. Enriched pathways and protein-protein interaction networks were identified. The correlation between host DNA methlytransferase-3A (DNMT3A) genotype and serum IL-10 level was examined in the identified GE modules. Upregulation of T and B cell immune response genes early during MRSA infection discriminate RB from PB patients. T and B cell signalling pathways were significantly increased in RB patients and correlated with lower serum IL-10 levels and the DNMT3A heterozygous A/C genotype. These findings indicate that patients with DNMT3A A/A genotypes have dysregulated adaptive immune responses characterized by impaired T and B cell function that increase the risk of PB outcome. These findings suggest that combining the genotype of the host with transcriptome and proteomic profiles might help determine the outcome of MRSA bacteremia. This knowledge may result in a better understanding of S. aureus pathogenesis and development of new anti-infective therapies and vaccines to improve patient outcomes. These studies were supported by in-part by the following NIH grants U01-AI124319, R01-AI068804 and R33-AI111661(to MRY) and U01-AI124319 and U19AL128913 (to EFR).