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Coinfection with <i>Candida</i> and <i>Staphylococcus</i> results in higher mortality in animal studies. However, the pathogenesis and interplay between <i>C. albicans</i> and <i>S. aureus</i> in bloodstream infections (BSIs) is unclear. This study determines the clinical features and outcomes of mixed <i>C. albicans</i>/<i>S. aureus</i> (CA/SA) BSIs and biofilm formation on pathogenesis during coinfection. Demographics and outcomes for mixed BSIs and monomicrobial candidemia were compared. Compared to 115 monomicrobial <i>C. albicans</i> BSIs, 22 patients with mixed CA/SA BSIs exhibited a significantly higher mortality rate and shorter survival time. In vitro and in vivo biofilm analysis showed that <i>C. albicans</i> accounted for the main biofilm architecture, and <i>S. aureus</i> increased its amount. Antibiotic tolerance in <i>S. aureus</i>, which adhered to <i>Candida</i> hyphae observed by scanning electron microscope, was demonstrated by the presence of wild-type <i>C. albicans</i> co-biofilm. Upregulation in exotoxin genes of <i>S. aureus</i> was evidenced by quantitative RT-PCR when a co-biofilm was formed with <i>C. albicans</i>. Mixed CA/SA BSIs result in a higher mortality rate in patients and in vivo surrogate models experiments. This study demonstrates that the virulence enhancement of <i>C. albicans</i> and <i>S. aureus</i> during co-biofilm formation contributes to the high mortality rate.