Purpose: To examine the cost-effectiveness of a series (total of 3 injections) of intra-articular platelet-rich plasma (PRP) injections in comparison to that of hyaluronic acid (HA) viscosupplementation for the treatment of symptomatic knee osteoarthritis. Methods: Outcome data regarding the use of PRP or HA injections for the treatment of symptomatic knee osteoarthritis were determined from the highest-quality data (Level I) available in the literature until 2015. Health utility values were then derived from these high-quality data. Costs were determined by examining typical charges for patients undergoing a series of either PRP or HA injections for the treatment of this condition at a large private orthopaedic practice. These health utility values and costs were used to create an expected-value decision analysis model. Results: The results of the model revealed that the cost per quality-adjusted life-year (QALY) of a series of PRP injections was $8,635.23/QALY and that of a series of HA injections was $5,331.75/QALY. A series of PRP injections was associated with a higher initial cost than a series of HA injections (difference, $1,433.67); however, PRP was also more effective (higher utility value) than HA by 0.11 QALYs (0.69 vs 0.58, P 1/4 .0062) at 1 year. The incremental cost-effectiveness ratio of the use of PRP injections as opposed to HA was $12,628.15/QALY. Conclusions: Although a series of either PRP ($8,635.23/QALY) or HA ($5,331.75/QALY) injections for the treatment of symptomatic knee osteoarthritis would be considered cost-effective (cost per QALY < $50,000), PRP injections were not more cost-effective than HA injections. However, PRP was significantly more effective at 1 year, and being associated with an incremental cost-effectiveness ratio of $12,628.15/QALY when compared with HA, a series of PRP injections should be considered a reasonable and acceptable alternative to HA injections for the treatment of symptomatic knee osteoarthritis.