INTRODUCTION: Local anesthetic blockade of the genicular nerves, known targets of radiofrequency ablative techniques for knee pain, has not previously been studied in a randomized controlled trial evaluating acute pain after knee arthroplasty. We hypothesized that genicular nerve blockade added to an existing block regimen in total knee arthroplasty would result in a reduction in 24 hours opioid consumption. METHODS: Patients (American Society of Anesthesiologists 1-3, aged 18-85 years) undergoing primary total knee arthroplasty were randomized to receive single-injection nerve blocks of the superolateral, superomedial, and inferomedial genicular nerves with injectate (15 mL 0.25% bupivacaine and 2 mg dexamethasone or 15 mL saline placebo). All subjects received a standard oral analgesic regimen, spinal anesthetic with 12.5 mg isobaric bupivacaine, infiltration between the popliteal artery and capsule of the knee with 0.2% ropivacaine, and postoperative adductor canal perineural infusion with 0.2% ropivacaine. The primary outcome was 24 hours opioid consumption (measured in morphine milliequivalents). RESULTS: Forty (40) subjects were enrolled. Opioid consumption at 24 hours was significantly lower in the BLOCK group compared with the SHAM group (23±20 vs 58±35, p<0.001), and this difference remained significant at 48 hours (50±40 vs 98±56, p=0.004). Pain scores were reduced in the BLOCK group at time 6 hours (2.6±1.9 vs 4.3±2.2, p=0.012), but were otherwise similar at remaining time points. Patient satisfaction at 24 hours and 20 m walk test times were similar between groups. DISCUSSION: Genicular nerve blockade was associated with a reduction in opioid consumption at 24 hours in primary total knee arthroplasty patients. TRIAL REGISTRATION NUMBER: NCT03706313.