The use of ceftriaxone for methicillin-sensitive Staphylococcus aureus (MSSA) osteoarticular infections in outpatient antimicrobial therapy remains controversial. Our informal survey of 135 academic and community infectious disease physicians suggests that only 96 (71.1%) are willing to use ceftriaxone for MSSA osteoarticular infections, 55 of which use it only infrequently (ie, 1%–19% of the time). Among the ceftriaxone users, most believe that there is a role for ceftriaxone in acute osteomyelitis (82.2%), chronic osteomyelitis (63.3%), osteomyelitis with uncomplicated bacteremia (61.1%), vertebral osteomyelitis (57.8%), and prosthetic infections (51.1%). We reviewed the clinical literature and analyzed ceftriaxone pharmacokinetics-pharmacodynamics to construct a clinical framework to optimally use ceftriaxone in osteoarticular infections. We conclude that ceftriaxone may be a reasonable therapeutic option for acute, uncomplicated MSSA osteoarticular infections after adequate surgical debridement, particularly when ceftriaxone is given as 2 g daily for MSSA isolates with oxacillin minimal inhibitory concentration values of 0.5 μg/mL or less (corresponding to ceftriaxone minimal inhibitory concentration values of ≤4 μg/mL).