Background: Betulinic acid, a natural pentacyclic triterpenoid, has been studied for its anti-inflammatory and anti-tumoural properties in various species. Recent in vitro and in vivo work has shown promise for treatment of equine skin tumours’ in horses. Objective: The objective of this study is to evaluate the safety and efficacy of a compounded 1% betulinic acid cream for the treatment of equine cutaneous melanoma and sarcoid in clinical cases. Study Design: Prospective randomized, blinded, placebo-controlled clinical trial. Methods: In select cases, biopsies were performed to confirm the diagnosis prior to enrolment. Photographs and measurements were obtained before and after the trial period. A compounded 1% betulinic acid or placebo cream was applied twice daily for 7 days, then once daily for 21 days. Owners completed a daily questionnaire to evaluate adverse reactions. Tumour volume was calculated based on width and length measurements using an established model. Mann-Whitney U tests were used to evaluate the change in tumour volume between groups. Results: A total of 37 horses completed the clinical trial, 16 horses with melanoma and 21 horses with sarcoid tumours. There were no significant differences in the change in tumour volume between treatment and placebo groups for either tumour type. The compounded cream was well tolerated. Main Limitations: This study was limited by owner subjectivity in application and questionnaires. Follow-up tumour measurements were not always performed by the same veterinarian. Conclusions: Based on this data, application of a compounded 1% betulinic acid cream was safe but did not result in a statically significant reduction in tumour volume for equine melanoma or sarcoid during a 30-day application period compared to a placebo. In general, tumour volume decreased in all groups and clinical trials evaluating the compound at twice daily application for an extended application period would be valuable.