Knee osteoarthritis is not always well controlled by usual treatments, therefore new therapeutic methods such as radiofrequency and ozone injection should be investigated. Comparing the efficacy of two methods: radiofrequency and intra-periarticular ozone injection. This randomized clinical trial study was performed in an academic Pain Clinic of Guilan University of Medical Sciences in Iran from September 2014 to June 2015. The research was carried out on seventy-two patients, were randomly allocated in two groups by triple blocks. thirty-six patients in ozone group received intra-periarticular ozone injection and 36 patients in RF group, after a positive diagnostic genicular nerve blocks received Conventional Radiofrequency(CRF)and then intra articular Pulse Radiofrequency(PRF). The evaluation was based on Visual Analog Scale (VAS) and Oxford Knee Score (OKS) before and 12 weeks after the procedure. The analysis was performed by paired t-test, Fisher, Chi square and Mann-Whitney-U tests in SPSS version18. In Ozone group the mean of initial OKS was 38.77±7.75 compare to 41.22±7.44 in RF group. After 12 weeks, it diminished to 21.77±7.78 and 22±6.21 respectively (p=0.0001). In Ozone group VAS decreased from 9±1.43 to 3.38±1.79 (p=0.0001) while in RF group from 9.44±0.85 to 2.77±1.06 (p=0.0001). Comparing two methods, there was no significant difference between two groups based on OKS(p=0.23) and VAS (p=0.202). Also RF resulted in more acceptable pain relief based on OKS among subjects older than 65 years (p=0.0001). Both radiofrequency and intra-periarticular ozone injection have good clinical effects on knee osteoarthritis with superiority of radiofrequency in age above 65 years old.