To evaluate the efficacy and safety of intraarticular propolis compared with systemic antibiotic treatment in an experimental septic arthritis model. Thirty-two rabbits were infected intraarticularly by Staphylococcus aureus. The rabbits were randomly divided into four groups, including a control group and three experimental groups. Drainage was the only procedure performed in group I (control group). The animals were treated with daily intramuscular cefazolin sodium (75 mg/kg) for 7 days in group II. In group III, intraarticular ethanolic extract of propolis (0.5 mg/ml) was injected to the infected knees under sterile conditions on days 7, 14, and 21 after drainage. In group IV, the rabbits received both intramuscular cefazolin sodium as in group II and intraarticular ethanolic extract of propolis as in group III. After 8 weeks, the animals were killed and joint histopathological and scanning electron microscopic parameters were assessed. The best clinical score was obtained in group IV. There were statistically significant differences among all the groups (P < 0.05). The highest total score of the histological examination was found in group I and the best total score was obtained in group IV. There were statistically significant differences among the groups when we evaluated the scores of the parameters as loss of chondrocytes, loss of matrix, and pannus in-growth (P < 0.05). But there was no significant difference among the groups for the scores of cloning of the chondrocytes (P > 0.05). The highest scanning electron microscopy score was found in group I and the best score was obtained in group IV. Our results confirm the safety and efficacy of intraarticular propolis and synergistic effect of propolis when used with cefazolin in an experimental septic arthritis model. J Pediatr Orthop B 20:8-13 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.