With the development of highly effective, well-tolerated third-generation aromatase inhibitors (AIs), these drugs will probably play an increasingly important role in all phases of breast cancer treatment. As a result, the impact of such hormonal agents on patients’ quality of life bears rigorous investigation. In a randomized, multicenter, single-blind cross-over study, the AIs letrozole and anastrozole were evaluated for quality of life, toxicity, and patient preference. A total of 72 patients were enrolled and were treated with each drug for a 4-week period, with a 1-week drug-free washout period before cross-over to the alternate agent. Assessments included the FACT-ES, toxicity, and patient preference. The FACT-ES is a validated questionnaire designed to measure quality of life of women with breast cancer who are being treated with endocrine therapies. Letrozole was superior to anastrozole with respect to both quality of life and toxicity evaluations. In addition, at the conclusion of the trial, reduced nausea, hot flashes, and abdominal discomfort caused almost twice as many patients to prefer to continue with letrozole therapy than with anastrozole. Data from this recent trial indicate that letrozole is better tolerated and provides better quality of life than anastrozole for women with metastatic breast cancer.