Our objective was to assess the efficacy and safety of combined 10.6 microm and 650 nm laser irradiation on patients with knee osteoarthritis (OA). Forty patients with OA were randomly allocated to an active laser group or to a placebo laser group (20 per group). They either received active or sham laser treatment at acupoint Dubi (ST 35) in a total of 12 sessions. There was significant difference between the two groups in the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score change from baseline after 2 weeks of treatment (P = 0.047). The pain reduction of the active laser treatment group was 49%, whereas that of the placebo control group was only 13%. However, due to the high patient drop-out rate, the 4-week assessment could not be analyzed. Combined laser treatment seems beneficial to patients with knee OA. However, due to the small sample size and the high drop-out rate of patients in the placebo group, a large sample-size clinical trial is warranted to determine further the therapeutic efficacy of the device.