There is considerable overlap in the initial clinical and laboratory presentations of acute septic arthritis and Lyme arthritis. The authors present a consecutive case series of 10 children with acute arthritis consistent with septic arthritis who ultimately were diagnosed with Lyme disease. Fifty percent presented with a fever of 38 degrees C or higher. The peripheral white blood cell count and differential were not elevated, but the erythrocyte sedimentation rate and the C-reactive protein were significantly elevated. The joint fluid cell count was elevated, with 91% neutrophils. Seven patients in this series underwent emergent joint irrigation and debridement for presumed septic arthritis. The authors suggest that in regions where Lyme disease is endemic, children who present with presumed septic arthritis should also be evaluated for Lyme disease. The authors also present a protocol for evaluation and management of these diagnostically challenging cases.