Background. Antistaphylococcal penicillins are the treatment of choice for methicillin-susceptible Staphylococcus aureus (MSSA) infection. Ceftriaxone can be dosed once daily and is less expensive for outpatient therapy than oxacillin. We compared patient outcomes of MSSA osteoarticular infections treated with ceftriaxone versus oxacillin. Methods. We conducted a retrospective cohort study of patients with MSSA osteoarticular infections at a tertiary care hospital from January 2005 to April 2010. We collected demographic, clinical, and outcome data including treatment-related adverse events. Successful treatment (clinical improvement; improved follow-up markers and imaging; no readmission for treatment) was compared at 3-6 months and >6 months after completion of intravenous antibiotics. Results. In total, 124 patients had an MSSA osteoarticular infection; 64 (52%) had orthopedic hardware involvement. Of those patients, 74 (60%) received ceftriaxone and 50 (40%) received oxacillin. Oxacillin was more often discontinued due to toxicity (9 of 50 [18%] oxacillin vs 3 of 74 [4%] ceftriaxone; P =. 01). At 3-6 and >6 months, data for 97 and 88 patients, respectively, were available for analysis. Treatment success was similar at 3-6 months (50 of 60 [83%] ceftriaxone vs 32 of 37 [86%] oxacillin; P =. 7) and >6 months (43 of 56 [77%] ceftriaxone vs 26 of 32 [81%] oxacillin; P =. 6). After intravenous antibiotics, 56 (45%) patients received long-term suppression with oral antibiotics (31 of 74 [42%] ceftriaxone vs 25 of 50 [50%] oxacillin; P =. 4).Conclusions.In this comparison of ceftriaxone versus oxacillin for MSSA osteoarticular infections, there was no difference in treatment success at 3-6 and >6 months following the completion of intravenous antibiotics. Patients receiving oxacillin were more likely to have it discontinued due to toxicity.