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Background: Equine sarcoids (ES) are the most common cutaneous tumors in equids. Systemic treatment options are sparse. Subcutaneous (SC) injections of Viscum album extract (VAE) demonstrate efficacy as a systemic treatment directed against ES. Objectives/Aim: To critically assess the therapeutic efficacy of orally administered VAE. Animals: Forty‐five ES‐affected, privately owned, 3–12 year‐old horses. Methods: A 3‐armed randomized placebo‐controlled, double‐blinded study was conducted in a double‐dummy design. Horses were subjected to oral administration and SC injections of either VAE or placebo (VAE oral/placebo SC, VAE SC/placebo oral, placebo oral/placebo SC) over a 7‐month treatment period. Primary endpoint was the change of baseline of a composite index of ES number and ES area after 14 months. Second endpoint was the clinical response. Results: No statistically significant difference in the composite endpoint between the 3 study arms was found. The primary endpoint showed 4 (27%) horses in the VAE oral group with complete ES regression, 3 (21%) in the VAE SC injection group, and 2 (13%) in the placebo group. The clinical response revealed complete or partial regression in 6 horses of the oral VAE group (40%), 4 of the SC injection group (29%), and 4 of the placebo group (25%). Direct comparison of oral VAE and placebo showed an odds ratio, stratified for prognosis of 2.16 (95%‐CI: 0.45–10.42) and a P‐value of 0.336. Conclusion and Clinical Importance: Oral administration of VAE is well tolerated. No statistically significant difference in the effectiveness of systemic VAE versus placebo against ES was found. [ABSTRACT FROM AUTHOR]