We examined the efficacy of the culture filtrate of Cryptococcus neoformans var. gattii (CneF) as a novel anti-inflammatory compound in experimental septic arthritis. Haematogenously infectious arthritis was induced in rats by a single intravenous injection of 109 CFU Staphylococcus aureus producing toxic shock syndrome toxin-1. CneF solution at two different doses (36 and 72 mg/kg, based on carbohydrate concentration) was administered intraperitoneally 2 h before bacterial inoculation in the prevention groups and simultaneously with the appearance of clinical signs in the therapeutic groups. CneF administration was continued at regular 48-h intervals for 10 injections. The results of clinical evaluation showed that CneF-treated rats were significantly protected from disease development compared with nontreated controls. This finding correlated with the results of histological and radiological assessments of the involved joints. Synovial hypertrophy, inflammatory cell infiltration, pannus formation and cartilage/bone destruction were found to be significantly decreased in the prevention and therapeutic groups compared with arthritic controls. The data suggest that CneF may have therapeutic potential in the treatment of septic arthritis.