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Treatment of unicameral bone cysts (UBC) in the humerus with drainage screws is scarcely reported in the literature. The aim of this retrospective study was to compare drainage screws and alternative treatment methods with respect to the number of required surgical procedures to achieve sufficient UBC healing, postoperative fractures/recurrences/complications, and radiological outcome. Medical archives of two tertiary orthopedic referral centers were screened for all patients who were treated surgically for humeral UBC in the period 1991–2015 with a histologically/cytologically confirmed diagnosis. Sex, age, all surgical procedures, fractures, complications, recurrences, and the final radiological outcome were compared between patients treated with drainage screws, elastic intramedullary nails, or curettage with optional grafting. The study included 106 operated patients with a mean age of 10.3 years, with a mean follow-up of 5.7 years. The average number of UBC-related surgical procedures in sex-matched and age-matched treatment groups was 2.7 with drainage screws, 2.8 with intramedullary nails, and 3.5 with curettage/grafting (P=0.54). Intramedullary nails (odds ratio 0.20) and older age (odds ratio for each year 0.83) predicted a lower risk of postoperative UBC recurrence. Patients with drainage screws had the highest UBC recurrence rates and the lowest rates of changed initial treatment method. There was no difference between the treatment groups in the postoperative fracture rate, complications, or the final radiological outcome. UBC treatment in the humerus therefore requires approximately three surgical procedures, irrespective of the treatment modality chosen. Adding an elastic intramedullary nail to a humeral UBC cyst may reduce recurrence risk and prevent further fractures. Level of Evidence: Level III – therapeutic retrospective comparative study.