Statins taken for cardiovascular indications by patients with breast cancer and lymphoma during doxorubicin treatment may attenuate left ventricular ejection fraction (LVEF) decline, but the effect of statins on LVEF among patients with no cardiovascular indications is unknown.A double-blind, placebo-controlled, 24-month randomized trial of 40 mg of atorvastatin per day administered to patients with breast cancer and lymphoma receiving doxorubicin was conducted within the National Cancer Institute Community Oncology Research Program across 31 sites in the United States. At pretreatment and then 6 and 24 months after initiating doxorubicin, we assessed left ventricular (LV) volumes, strain, mass, and LVEF through cardiac magnetic resonance imaging, along with cognitive function and serum markers of inflammation. The primary outcome was the difference in 24-month LVEF between placebo and treatment groups, adjusted for pretreatment LVEF.A total of 279 participants were enrolled in the trial. Participants had a mean (±SD) age of 49±12 years; 92% were women; and 83% were White. The mean (±SD) LVEF values were 61.7±5.5% before treatment and 57.4±6.8% at 24 months in the placebo group and 62.6±6.4% before treatment and 57.7±5.6% at 24 months in the atorvastatin group. On the basis of a multiple imputed data set for missing data and adjusted for each individual's pretreatment LVEF, 24-month declines in LVEF averaged 3.3±0.6 percentage points and 3.2±0.7 percentage points, for those randomly assigned to placebo versus statins, respectively (P=0.93). Across both treatment arms, similar percentages of individuals experienced changes of more than 10 percentage points in LVEF, LV strain, LV mass, cognition, and inflammation biomarkers, including among those with greater than 90% drug compliance.In patients with breast cancer and lymphoma with no existing indication for statin therapy, prospective statin administration did not affect LVEF declines 2 years after doxorubicin. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01988571.).