The intramuscular application of etofenamate in the treatment of knee osteoarthritis was not observed in the existing English language literature. The objectives of this study were to compare the efficacy of etofenamate versus hyaluronic acid (HA) in reducing joint pain and functional improvement for mild to moderate knee osteoarthritis. The patients were randomly divided into etofenamate (n=29) and HA (n=30) groups. Intramuscular etofenamate injection was administered as a series of seven intramuscular injections at intervals of 1 day. Intra-articular HA injection was administered as a series of three intra-articular injections at intervals of 1 week. Clinical evaluation was made before the first injection and again both 6 and 12 months after the last injection. The evaluation consisted of patient-assessed pain on a visual analog scale (VAS) and on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Statistical significance was found for the etofenamate group when comparing preinjection with 12 months postinjection VAS scores (<0.05). Statistical significance was also found for the HA group when comparing preinjection with 12 months postinjection VAS and WOMAC scores (<0.05). However, there was no significant difference between the etofenamate and HA groups in terms of VAS or WOMAC scores measured at 12 months after injection (>0.05). Results from this study indicated that, etofenamate treatment was not significantly more effective than HA treatment. However, both methods were effective and successful in treating knee osteoarthritis.