Septic arthritis in children can be difficult to diagnose and may be associated with severe morbidity. A majority of apparent septic arthritis cases may have negative culture, thereby creating a dilemma regarding treatment. The medical charts of 209 children with the diagnosis of septic arthritis were retrospectively reviewed to evaluate the differences between culture-negative (n = 64) and culture-positive (n = 145) cases. Demographic data, clinical manifestations, treatment, and outcome were analyzed. Laboratory data recorded included white blood cell count, erythrocyte sedimentation rate, C-reactive protein, imaging studies, and culture results. Patients with culture-negative arthritis had a significantly lower incidence of fever (56.3% vs 70.3%, p=0.047), local pain or tenderness (42.2% vs 69.7%, p=0.0001), changes in the overlying skin (45.3% vs 62.1%, p=0.024), motion limitation (25.0% vs 42.8%, p=0.014), and osteomyelitis (25.0% vs 40.7%, p=0.029). Culture-negative patients had a longer duration of symptoms or signs before diagnosis (10.1 +/- 8.9 days vs 6.5 +/- 5.7 days, p=0.046) and a shorter antimicrobial course (24.5 +/- 5.1 days vs 35.7 +/- 8.1 days, p=0.001). Children with culture-negative septic arthritis had a lower prevalence of residual joint dysfunction at 6 months after treatment (3.1% vs 11.7%, p=0.046). In conclusion, children with culture-negative septic arthritis have milder clinical manifestations, earlier response to treatment, and a better outcome than those with culture-positive disease.