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The purpose of this systematic review was to synthesize the available Level I and Level II literature on platelet-rich plasma (PRP) as a therapeutic intervention in the management of symptomatic knee osteoarthritis (OA).A systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, PubMed, and www.clinicaltrials.gov was performed to identify all randomized controlled trials and prospective cohort studies that evaluated the clinical efficacy of PRP versus a control injection for knee OA. A random-effects model was used to evaluate the therapeutic effect of PRP at 24 weeks by use of validated outcome measures (Western Ontario and McMaster Universities Arthritis Index, visual analog scale for pain, International Knee Documentation Committee Subjective Knee Evaluation Form, and overall patient satisfaction).Six Level I and II studies satisfied our inclusion criteria (4 randomized controlled trials and 2 prospective nonrandomized studies). A total of 577 patients were included, with 264 patients (45.8%) in the treatment group (PRP) and 313 patients (54.2%) in the control group (hyaluronic acid [HA] or normal saline solution [NS]). The mean age of patients receiving PRP was 56.1 years (51.5% male patients) compared with 57.1 years (49.5% male patients) for the group receiving HA or NS. Pooled results using the Western Ontario and McMaster Universities Arthritis Index scale (4 studies) showed that PRP was significantly better than HA or NS injections (mean difference, -18.0 [95% confidence interval, -28.8 to -8.3]; P.001). Similarly, the International Knee Documentation Committee scores (3 studies) favored PRP as a treatment modality (mean difference, 7.9 [95% confidence interval, 3.7 to 12.1]; P.001). There was no difference in the pooled results for visual analog scale score or overall patient satisfaction. Adverse events occurred more frequently in patients treated with PRP than in those treated with HA/placebo (8.4% v 3.8%, P = .002).As compared with HA or NS injection, multiple sequential intra-articular PRP injections may have beneficial effects in the treatment of adult patients with mild to moderate knee OA at approximately 6 months. There appears to be an increased incidence of nonspecific adverse events among patients treated with PRP.Level II, systematic review of Level I and II studies.