Objectives: Combination of glucosamine-chondroitin sulfate is often prescribed for patients with first and second grade Kellgren-Lawrence osteoarthritis (OA). Numerous studies have reported significant efficacy of this supplement and also their combinations with methylsulfonylmethane (MSM) for the treatment of OA. However, controversies emerged regarding the effectiveness of these supplements. This current study evaluated the efficacy of glucosamine-chondroitin sulfate and glucosamine-chondroitin sulfate-MSM on improvement of patients with first and second grade knee OA. Methods: This study was a double blind, randomized controlled clinical trial on 147 patients with first and second grade (Kellgren-Lawrence) of knee OA. Subjects were allocated by permuted block randomization to three groups, either glucosamine-chondroitin sulfate (GC) (n=49), or glucosamine-chondroitin sulfate-MSM (GCM) (n=48), or placebo (n=50). The GC group received 1500 mg glucosamine + 1200 mg chondroitin sulfate + 500 mg saccharum lactis; GCM group received 1500 mg glucosamine + 1200 mg chondroitin sulfate + 500 mg MSM; while placebo group received three matching capsules of saccharum lactis. These drugs were administered once a day for three consecutive months. VAS and WOMAC score were measured at the baseline, then at 12th week after treatment. Data was analysed by using t-independent test. Results: At week 12, WOMAC score in placebo group was significantly higher than that in GCM group (mean difference 7.15, CI 12.06-2.23, p=0.005), and it was also higher in GC group compared to GCM group (mean difference 8.17, CI 13.49-2.84, p=0.003). Whereas VAS score at week 12 in placebo group was significantly higher compared to that in GC group (mean difference 0.18, CI 1.18-0.19, p=0.007) and to that in GCM group (mean difference 0.86, CI 1.37-0.35, p=0.001). However, there was no significant difference of WOMAC score at week 12 between placebo and GC groups (p=0.681), and of VAS score between GC and GCM groups (p=0.497). Conclusion: Combinations of glucosamine-chondroitin sulfate and glucosamine-chondroitin sulfate-MSM did not improve WOMAC and VAS scores in patients with grade I and II of knee osteoarthritis, when compared with placebo.