68 randomized controlled studies evaluating the effects of intra-articular hyaluronic acid injections in patients with knee osteoarthritis were selected for inclusion. The purpose of this meta-analysis was to compare the safety and efficacy of differing hyaluronic acid preparations for the treatment of knee osteoarthritis. The results displayed the greatest pain efficacy in high-molecular-weight hyaluronic acid products, yet this group also had significantly more flare-ups when compared to other treatments. High-molecular-weight preparations were correlated with less discontinuation due to adverse events, and biological fermentation-derived hyaluronic acid was associated with a superior safety profile compared to avian-derived hyaluronic acid.