Introduction. Staphylococcus spp. represent the leading cause of hospital-acquired infections and second-most frequent pathogen in bloodstream infections. Methicillin-susceptible S. aureus (MSSA) comprise approximately half of all S. aureus isolates. Standard-of-care therapies (SOCTs) display high treatment success but require frequent dosing, are problematic in penicillin allergic patients, and are nephrotoxic. Ceftriaxone may represent an alternative treatment option. Methods. Adult patients hospitalized from January 2015 through June 2016 with positive MSSA blood cultures and treated with SOCT or ceftriaxone for ≥48 hours were included. Exclusion criteria were receipt of vancomycin or concomitant systemic antimicrobials with activity against MSSA, polymicrobial infections, and pregnant patients. Additional data collected included demographics, source/site of infection, and treatment. The primary endpoint was clinical cure (normalization of white blood cell count and temperature within 7 days and clearance of bloodstream within 7 days). Readmission within 60 days, length of stay, and discharge disposition were collected. Results. A total of 43 patients were included: 23 receiving SOCT and 20 receiving ceftriaxone group. Sixteen patients received SOCT prior to ceftriaxone while 4 patients were initiated on ceftriaxone. Clinical cure was observed in 18/23 (78%) and 10/20 (50%), respectively ( P = 0.052 ). Clinical failure was driven by leukocytosis despite clearance of their bloodstream infection in 3/23 (13%) SOCT group compared to 8/20 (40%) in the ceftriaxone group ( P = 0.043 ). Six patients (SOCT: 2, ceftriaxone: 4; p = 0.669 ) had infection-related readmissions, and 1 death per group was observed. Conclusion. Ceftriaxone poses a reasonable alternative to consider for MSSA bacteremia when cost and feasibility are concerns for outpatient parenteral therapy after initial clearance of bloodstream infections.