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Staphylococcus aureus is the most common cause of septic arthritis (SA) in children. USA300 is the predominant community methicillin-resistant (MRSA) clone. Panton-Valentine leukocidin genes (pvl) have been associated with severe disease.Patients with S. aureus SA were identified from the Texas Children's Hospital surveillance study. Pulsed field gel electrophoresis and pvl polymerase chain reaction were performed on isolates.Forty-five patients with S. aureus SA were identified between August 2001 and October 2008. Median age was 5.5 years (0.3–17.9 years); 69% were previously healthy. The most common joints affected were hip (40%) followed by knee (36%). Associated infection sites were osteomyelitis (n = 14), pyomyositis/myositis (n = 13), and cellulitis (n = 9). Bacteremia for 1 to 5 days occurred in 31% of the patients. Patients with associated osteomyelitis were more likely to be bacteremic (P = 0.001), have fever >2 days (P = 0.03), and to have C-reactive protein (CRP) ≥10 mg/dL (P = 0.01). Of 44 available isolates, 16 were MRSA; 13 of 16 were USA300 and 14 of 16 were pvl+. Twenty-eight isolates were MSSA; 8 of 28 were USA300 and 13 of 28 were pvl+. Infections caused by USA300 isolates were associated with longer duration of fever than non-USA300 isolates (median, [range]: 4 [0–15] days vs 1 [0–8] days) (P = 0.03). Overall, 61% of the isolates were pvl+. CRP ≥10 mg/dL was more likely in pvl+ infections than in pvl− infections (P = 0.05).S. aureus SA caused by USA300 isolates is associated with longer duration of fever. Empirical treatment of SA should include MRSA. CRP levels ≥10 mg/dL, fever >2 days, and bacteremia should raise suspicion for associated osteomyelitis.