PURPOSE: Treatment of chronic pain associated with occipital neuralgia (ON) is complex, and no consensus statement or guidelines have been published for ON management. This pilot study evaluated the efficacy and safety of cryoneurolysis for management of ON-associated chronic pain. PATIENTS AND METHODS: The study was a prospective, multicenter, nonrandomized cohort study assessing the degree and duration of clinical effect of cryoneurolysis therapy for reducing pain in patients diagnosed with unilateral or bilateral ON. The primary outcome measure was improvement in pain due to ON from baseline to day 7, measured on an 11-point numeric rating scale for pain. Secondary outcome measures included duration of treatment effects and safety events, including anticipated observations and adverse events. Treatment effect was assessed at days 7, 30, and 56 by asking the patient if they were continuing to experience a treatment effect, with potential responses of "effect," "no effect," or "no longer effective." A posttreatment questionnaire evaluated patient satisfaction. RESULTS: Twenty-six patients (9 men, 17 women) with a mean age of 49.1 years enrolled and completed the study. A total of 64% (16/25) of participants reported a clinically important improvement of ≥2 points in numeric rating scale pain scores at day 7; similar results persisted to day 30. Treatment effects were reported by 50% (13/26) of participants at day 30, with a continued effect reported by 35% (9/26) of participants at day 56. Overall, ~70% of participants were satisfied with treatment at 7, 30, and 56 days. No serious anticipated observations, adverse events, or unanticipated adverse device effects were reported. CONCLUSION: Cryoneurolysis provided significant relief from pain associated with ON ≤30 days after treatment and had an acceptable safety profile.