Although accepted as a conservative treatment option for knee osteoarthritis, the debate about the effectiveness of intra-articular treatment with hyaluronic acid (HA) is still ongoing because of contrasting outcomes in different clinical studies. Several well designed clinical studies showed a significant improvement in pain at follow-up compared with baseline but no significant improvement comparing the efficacy of HA with placebo (saline) or with other conservative treatment options. Notwithstanding the effectiveness of different types of intra-articular HA products, the question of whether one HA product is better than another is still unanswered. In this systematic review we compare the effects of intra-articularly administered HA with intra-articularly administered placebo in general and, more specifically, the effects of individual HA products with placebo. We also compare the efficacy of different HA products.