AIM: Simple hepatic cysts are typically benign; however, when they are large and symptomatic, therapeutic intervention is required. We previously reported our initial experience with ultrasound (US)-guided polidocanol foam sclerotherapy in three patients with symptomatic giant hepatic cysts. In the present study, we examined the efficacy and safety of polidocanol foam sclerotherapy in a larger number of patients with long-term follow-up. METHODS: Between May 2016 and April 2021, 15 patients with symptomatic giant hepatic cysts were referred to our hospital. All patients were prospectively included in the study and underwent US-guided polidocanol foam sclerotherapy. RESULTS: The mean maximum diameter and estimated cyst volume were 128.4 mm (77-223 mm) and 922.3 mL (123.2-2797 mL), respectively. Polidocanol foam was successfully administered through an 8.5-Fr pigtail catheter in all patients. The percentages of cyst diameter/volume after 1-3 months, 3-6 months, 6 months-1 year, 1-2 years, and 2-4 years of sclerotherapy were 66.8%/36.5%, 48.1%/14.8%, 34.1%/6.9%, 28.2%/3.7%, and 26.2%/3.1%, respectively. During the follow-up period, there were no cases of symptom recurrence or need for additional treatment due to cyst re-growth. Six patients (40%) had fever, one had nausea, and one had right-sided chest pain, but none of these adverse events required prolonged hospitalization or readmission. CONCLUSIONS: US-guided polidocanol foam sclerotherapy may be an effective and safe method for the treatment of symptomatic giant hepatic cysts. This article is protected by copyright. All rights reserved.