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Optimal analgesia for total knee arthroplasty remains challenging. Many modalities have been used, including peripheral nerve block, periarticular infiltration, and epidural analgesia. However, the relative efficacy of various modalities remains unknown. The authors aimed to quantify and rank order the efficacy of available analgesic modalities for various clinically important outcomes.The authors searched multiple databases, each from inception until July 15, 2016. The authors used random-effects network meta-analysis. For measurements repeated over time, such as pain, the authors considered all time points to enhance reliability of the overall effect estimate. Outcomes considered included pain scores, opioid consumption, rehabilitation profile, quality of recovery, and complications. The authors defined the optimal modality as the one that best balanced pain scores, opioid consumption, and range of motion in the initial 72 postoperative hours.The authors identified 170 trials (12,530 patients) assessing 17 treatment modalities. Overall inconsistency and heterogeneity were acceptable. Based on the surface under the cumulative ranking curve, the best five for pain at rest were femoral/obturator, femoral/sciatic/obturator, lumbar plexus/sciatic, femoral/sciatic, and fascia iliaca compartment blocks. For reducing opioid consumption, the best five were femoral/sciatic/obturator, femoral/obturator, lumbar plexus/sciatic, lumbar plexus, and femoral/sciatic blocks. The best modality for range of motion was femoral/sciatic blocks. Femoral/sciatic and femoral/obturator blocks best met our criteria for optimal performance. Considering only high-quality studies, femoral/sciatic seemed best.Blocking multiple nerves was preferable to blocking any single nerve, periarticular infiltration, or epidural analgesia. The combination of femoral and sciatic nerve block appears to be the overall best approach. Rehabilitation parameters remain markedly understudied.