329 patients with symptomatic knee osteoarthritis (OA) were randomized to receive either Low Molecular Weight Fraction of 5% human serum albumin (LMWF-5A) or saline vehicle solution, each at a dose of either 4 or 10 mL. The purpose of this study was to determine the analgesic efficacy and safety of LMWF-5A in this study population. Results indicated that both the 4-mL and 10-mL volumes of the LMWF-5A solution were safe and yielded significantly better pain scores, functional outcome, and overall assessment of disease severity, when compared to a saline vehicle solution. These effects were especially pronounced in patients with severe OA, and those who received a prior knee injection.