Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. The hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. Currently there is no licenced specific treatment for alphavirus disease and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Paradigm Biopharmaceuticals Ltd is currently developing Zilosul® (pentosan polysulfate; PPS) for the treatment of a number of disease pathologies. Our preclinical findings using a mouse model show RRV infection damages the articular cartilage including a loss of proteoglycans within joint, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. Reduction in cartilage damage corresponded with a significant reduction in joint inflammation. Excitingly, Paradigm’s followon Phase II randomised, double-blinded placebo-controlled clinical trial in participants with RRV has supported the preclinical findings with success in both its primary (safety) and secondary (improvement in disease) endpoints. This includes demonstrating both clinical and statistical improvements in joint pain/arthralgia, hand grip strength and in overall quality of life. Currently further analysis of patient biomarkers is underway with promising preliminary findings demonstrating additional positive effects of PPS treatment. Given the results of this study and the positive and extensive long-term human safety data on PPS, we propose PPS is a promising candidate for the treatment of alphavirus-induced arthritis.