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Background: While the current guidelines recommend laparoscopic deroofing for symptomatic simple liver cysts, percutaneous drainage may serve as a less invasive alternative method. In this study, the treatment effects of percutaneous drainage with or without sclerotherapy for symptomatic simple liver cysts were evaluated. Methods: Between April 2016 and March 2021, 79 patients who initially required hospitalization due to symptomatic simple liver cysts were enrolled in this multicenter retrospective study. They were treated percutaneously with or without sclerotherapy. The factors associated with symptom recurrence, clinical course and prognosis were investigated. Results: Of the 79 patients treated percutaneously, 11 (13.9%) had symptom recurrence due to liver cysts during the observation period. The maximum diameter of liver cysts at baseline was the only significant factor for the recurrence of these symptoms (p = 0.004). In a receiver operating characteristics analysis, the cut-off of the diameter for symptom recurrence was 16.5 cm. No additional effect of sclerotherapy on drainage was demonstrated in patients with a cyst diameter of <16.5 cm, and in patients with a cyst diameter of ≥16.5 cm, the cumulative recurrence rates of symptoms were significantly lower in the patients treated via sclerotherapy with 5% ethanolamine oleate or with minocycline hydrochloride than in those treated with drainage alone or via sclerotherapy with absolute ethanol. No problematic adverse effects were observed of sclerotherapy. Conclusions: Drainage with sclerotherapy with 5% ethanolamine oleate or minocycline hydrochloride was an effective and safe treatment for patients whose liver cysts had a maximum diameter of ≥16.5 cm. Considering both its efficacy and safety, sclerotherapy with either of these agents is recommended for patients with a maximum liver cyst diameter of ≥16.5 cm.