Objective: To investigate whether the number of hyaluronic acid (HA) injections in a sodium hyaluronate (Hyalgan) course of therapy alters effectiveness in reducing knee osteoarthritis (OA) pain. Data Sources: Electronic databases, including PubMed and Embase, were searched from January 1980 until November 2015. Study Selection: We included clinical studies that evaluated the effectiveness of a course of 3 or 5 weekly intra-articular injections of Hyalgan to treat knee OA pain. We also included clinical studies evaluating the effectiveness of a 3-week course of other Food and Drug Administration approved HA treatments of knee OA pain. Twenty-four studies were identified, comprising 2168 study participants in 30 treated cohorts. Data Extraction: We determined effect sizes for selected studies by extracting knee OA pain scores before and after HA or control treatments. Meta-regressions were implemented to determine whether the number of weekly injections in a course of Hyalgan therapy modified outcomes. Data Synthesis: The pooled estimate for relief from baseline pain was -31.4 (SE, 5.46; 95% confidence interval [CI], -45.5 to -17.4) with a 3-week course of Hyalgan and -32.2 (SE, 5.25; 95% CI, -45.6 to -18.7) with a 5-week course of Hyalgan. Findings from the meta-analysis indicate relief of knee OA pain with a 3-week course of Hyalgan is similar to that with a 5-week course of Hyalgan (P=.916). The pooled estimate for relief from baseline pain with a 3-week course of other HA products was -29.4 (SE, 4.98; 95% CI, -42.2 to -16.6), also indicating pain relief with a 3-week course of Hyalgan is similar to that with a 3-week course of other HA products (P=.696). Conclusions: There was no statistical difference between reduction in knee OA pain with a 3-week course of Hyalgan compared with reduction in knee OA pain with a 5-week course of Hyalgan or a 3-week course of other HA products. These findings demonstrate that comparable knee OA pain relief is achieved with a 3-week course of Hyalgan and the 2 control groups. (C) 2017 by the American Congress of Rehabilitation Medicine