One hundred and eighty patients with mild-to-moderate knee osteoarthritis (OA) were randomized to receive cryoneurolysis (n=121) or sham treatment (n=59) for pain management and symptom relief. The primary outcome of interest was pain scores using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) measured at 30 days post-treatment. Secondary outcomes of interest included pain on the visual analogue scale (VAS) and total WOMAC scores measured at 30, 60, 90, and 120 days post-treatment. Both primary and secondary outcomes were measured as the average of the mean change from baseline. Other outcomes of interest included WOMAC function and stiffness subscores, incidence of adverse events, the 36-item Short Form Health Survey (SF-36), and the Patient Global Impression of Change (PGIC). All outcomes were measured at days 30, 60, 90, and 120 post-treatment and if a significant effect was observed at day 120, then primary and secondary outcomes were additionally measured at days 150, and 180 post-treatment. Results revealed a significantly greater and favorable change from baseline at 30 days post-treatment in WOMAC pain score in the cryoneurolysis group vs sham (p=0.0004) and this trend continued until day 90 (p<0.05) post-treatment but not beyond that. Similar results were observed in favour of the cryoneurolysis group for WOMAC total score. Moreover, for VAS pain, a significantly greater change from baseline was observed at day 30 in the cryoneurolysis group vs sham group (p=0.0073), not at any other timepoints (p>0.05 for all).