BACKGROUND Standard analgesic strategies for total knee arthroplasty employ local infiltration analgesia. Blockade and radiofrequency ablation of the genicular nerves are effective treatments for patients with chronic pain because of knee osteoarthritis. OBJECTIVE To test the noninferiority of the analgesic effect of genicular nerves block in comparison with local infiltration analgesia after 24 h of total knee arthroplasty. DESIGN Prospective cohort study. SETTING Perioperative setting. PATIENTS Thirty-five patients scheduled for total knee arthroplasty were prospectively included in the study and compared with 35 patients in a retrospective cohort. INTERVENTION Genicular nerve blocks in the prospective cohort were compared with local infiltration analgesia in the retrospective cohort. MAIN OUTCOME MEASURES The pain numeric rating scale and the cumulative opioid consumption in oral morphine equivalents during the first 24 h. RESULTS We conducted propensity score-matched analyses of patients using acute postoperative pain-related risk covariates. After one-to-one propensity score matching, 21 patients were included in the local infiltration analgesia group and 21 in the genicular nerve block group. The median difference in numeric rating score at rest at 24 h was −0.99 [95% confidence interval (CI), −1.99 to 0.5, P = 0.012] on the unmatched cohort and −1.9 (95% CI, −2 to 0, P = 0.002) on the matched cohort (meeting the noninferiority criteria, Δ=1). The median difference in cumulative opioid consumption was 2.5 mg (95% CI, −13.5 to 2.5, P < 0.001) for the unmatched cohort and 4.99 mg (95% CI, −11.5 to 2.5, P < 0.001) on the matched group (meeting the noninferiority criteria, Δ = 21 mg). CONCLUSION Local infiltration analgesia and genicular nerve block are comparable in terms of analgesic results. Therefore, genicular nerves block is an alternative to local infiltration analgesia in patients undergoing total knee arthroplasty. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT04024319.