Purpose The Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) -positive and node-positive early breast cancer (eBC). Methods Postmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety. Results A total of 4,136 patients were randomly assigned to receive either letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for letrozole versus 82.9% for anastrozole arm (hazard ratio, 0.93; 95% CI, 0.80 to 1.07; P = .3150). Exploratory analysis showed similar DFS with letrozole and anastrozole in all evaluated subgroups. The 5-year estimated overall survival rate was 89.9% for letrozole versus 89.2% for anastrozole arm (hazard ratio, 0.98; 95% CI, 0.82 to 1.17; P = .7916). Most common grade 3 to 4 adverse events (> 5% of patients) reported for letrozole versus anastrozole were arthralgia (3.9% v 3.3%, and 48.2% v 47.9% for all adverse events), hypertension (1.2% v 1.0%), hot flushes (0.8% v 0.4%), myalgia (0.8% v 0.7%), dyspnea (0.8% v 0.5%), and depression (0.8% v 0.6%). Conclusion Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in postmenopausal patients with HR-positive, node-positive eBC.