Osteoarthritis (OA) of the knee is one of the most relevant and debilitating health problems. Obesity represents one of the major risk factor for early development of OA. In the obese population, knee replacement should be delayed and eventually avoided and prefer conservative treatments including intrarticular hyaluronic acid (HA) viscosupplementation. In the present clinical randomized trial, we present a comparison between two groups of 24 obese patients which were randomized to be treated with two intrarticular injections of hybrid (low and high molecular weight) hyaluronic acid (Group A) or two injections of high molecular weight hyaluronic acid (Group B). Patients were followed-up through to 6 months and assessed though IKDC and KOOS scores, pain was evaluated with VAS. All patients reported a significant improvement when compared to baseline value in all outcome measures. At 3-month follow-up, IKDC had significantly improved in patients of Group A, compared to Group B (53.1±1.9 vs 51.4±2.4, p=0.0079) and the same for KOOS (52.1±2.0 vs 50.1±2.9, p=0.010). Furthermore, the difference in KOOS was persistently significant at 6-month follow-up (54.7±2.3 vs 51.7±4.9, p=0.014). The VAS reduced significantly more in Group A at 3 months (3.7±0.5 vs 5.2±0.7, p less than 0.001). In an obese population, where basal inflammatory pattern increases symptoms of OA and conservative treatment is recommended, HA viscosupplementation improved function and pain of the knee. The treatment with hybrid HA showed better outcomes than high molecular weight HA in obese patients. The combination of the anti-inflammatory action of low molecular weight HA on chondrocytes and the biomechanical role of high molecular weight HA might explain the different results.