BACKGROUND: The objective was to investigate whether cryoneurolysis was superior to sham in reducing pain intensity in patients with chronic knee osteoarthritis. The hypothesis was that cryoneurolysis is an effective and safe therapy to reduce chronic pain in patients with knee osteoarthritis. METHODS: The study was randomized, double blind, and sham controlled. A total of 87 patients with chronic knee osteoarthritis were randomized to either cryoneurolysis or a sham procedure, followed by an exercise program. The target nerves, anterior femoral cutaneous nerve and infrapatellar branch of the saphenous nerve were identified using transcutaneous electrical nerve stimulation, and cryoneurolysis was performed with ultrasound guidance. The primary outcome was the difference in average pain at 14 days after intervention between the cryoneurolysis and sham group. RESULTS: For the intention-to-treat analysis, no difference was observed for the primary outcome (0.49; 95% CI, -0.3 to 1.2; P = 0.198). Both groups showed a significant reduction in pain scores 14 days after intervention (cryoneurolysis: -1.9; 95% CI, -2.4 to -1.3; and sham: -1.4; 95% CI, -1.9 to -0.8). At 6-month follow-up, a significant reduction in pain was observed in the cryoneurolysis group compared to the sham group (1.1; 95% CI, 0.3 to 1.9; P = 0.009). Cryoneurolysis was well tolerated, with minor, transient adverse effects. CONCLUSIONS: This study did not show a clinically relevant reduction in pain after intervention comparing cryoneurolysis and sham. Further studies are needed.