OBJECTIVE: Hot flashes are a common symptom in breast cancer survivors that can negatively impact quality of life. Preliminary data suggested that magnesium might be used as an effective low-cost treatment of hot flashes with minimal adverse effects. METHODS: A four-arm, double-blind, placebo-controlled, randomized trial was conducted. Postmenopausal women with a history of breast cancer and bothersome hot flashes were randomized into treatment groups of magnesium oxide 800 or 1,200 mg daily or corresponding placebo groups at a 2:2:(1:1) ratio. Hot flash frequency and hot flash score (number x mean severity) were measured using a validated hot flash diary. A 1-week baseline period preceded initiation of study medication. The primary endpoint was intrapatient difference in mean hot flash score between baseline and treatment periods, comparing each magnesium group with the combined placebo groups using a gatekeeping procedure. Results were analyzed using repeated-measures and growth curve models on weekly hot flash scores based on a modified intent-to-treat principle. RESULTS: Two hundred eighty-nine women enrolled between December 2011 and March 2013. Study groups were well balanced for baseline characteristics. Mean hot flash scores, mean hot flash frequencies, and associated changes during the treatment period were similar for each group. An increased incidence of diarrhea and a corresponding lower incidence of constipation were reported in magnesium arms compared with placebo. No statistically significant difference in other toxicities or quality-of-life measures was observed. CONCLUSIONS: The results of this trial do not support the use of magnesium oxide for hot flashes.