Introduction: Recent evidence has shown that oral antibiotic therapy is not inferior to IV antibiotic therapy in the treatment of complicated Staphylococcus aureus infections. Therefore, oral antibiotic therapy is now frequently prescribed in clinical practice due to cost benefit, ease of administration, decrease complications rate and lack of need for an IV access. In vitro susceptibility testing for β-lactam oral antibiotics is not routinely performed as the guidelines provided by Clinical and Laboratory Standards Institute (CLSI) recommend using oxacillin and cefoxitin as surrogate markers. Hence, oral antibiotic susceptibilities for cephalexin and dicloxacillin are not reported and implied based on oxacillin and cefoxitin. The objective of the current study was to determine whether susceptibilities among S. aureus isolates is predictable when comparing commonly used IV and oral beta-lactams. Methods: Cefazolin, cephalexin, dicloxacillin and oxacillin broth microdilution minimum inhibitory concentrations (MICs) were determined for 100 clinical isolates of methicillin-sensitive S. aureus (MSSA) by broth microdilution following CLSI guidelines. Results: Among these isolates, median MICs for cephalexin were eight-fold higher than cefazolin MICs and median MICs for dicloxacillin were four-fold less than oxacillin MICs. Ten percent of more strains studied had a major or very major error in its susceptibility reporting when cephalexin was compared to its surrogate marker oxacillin. Discussions/Conclusions: The variations in MICs observed compounded with the dosing and pharmacokinetic differences of oral vs IV β-lactam suggests that establishing breakpoints for oral β-lactam antibiotics is necessary to ensure adequate therapy is selected for the treatment of complex S. aureus infections.