Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS). Between 1993 and 2002, women > or = 60 years old with clinically node-negative operable breast cancer in whom adjuvant tamoxifen was considered indicated regardless of pathologic nodal status were randomly assigned to primary surgery plus axillary clearance (Sx + Ax) followed by tamoxifen (Tam) versus Sx without Ax followed by Tam for 5 consecutive years. The primary end point was QL reported by the patient and by physician assessment. A total of 473 patients (234 to Sx + Ax, 239 to Sx) were randomly assigned. The median age was 74 years; 80% had estrogen receptor-positive disease. In both the patients' subjective assessment of their QL and the physicians' perception of the patients' QL, the largest adverse QL effects of Ax were observed from baseline to the first postoperative assessment, but the differences tended to disappear in 6 to 12 months. At a median follow-up of 6.6 years, results for Sx + Ax and Sx yielded similar DFS (6-year DFS, 67% v 66%; hazard ratio HR Sx + Ax/Sx, 1.06; 95% CI, 0.79 to 1.42; P = .69) and OS (6-year OS, 75% v 73%; HR Sx + Ax/Sx, 1.05; 95% CI, 0.76 to 1.46; P = .77). Avoiding axillary clearance for women > or = 60 years old who have clinically node-negative disease and receive Tam for endocrine-responsive disease yields similar efficacy with better early QL.