Background: Older adults with multiple comorbidities and poor functional status may not be appropriate candidates for chemotherapy. We conducted a phase II trial to examine the safety and efficacy of single-agent Trastuzumab for older women with early stage Human Epidermal Growth Factor Receptor Type 2 (Her2)-positive breast cancer. Methods: This was a single-arm open label multi-institutional clinical trial of adjuvant single-agent Trastuzumab in women aged ≥ 60 years with stage I-III Her2-positive breast cancer who had either declined chemotherapy or were not chemotherapy candidates. Patients received Trastuzumab monotherapy, (8 mg/kg) for cycle 1 followed by (6 mg/kg) every 3 weeks for 12 months. The primary end point was one-year cumulative incidence of symptomatic congestive heart failure with reduced ejection fraction (HFrEF). Secondary endpoints were disease free survival (DFS) and overall survival (OS) at 5 years. Results: Fifty-six patients were enrolled across four centers with a median follow-up period of 5.0 years, (range 0-6.5). The median age was 72.5 years (range 60-90), 64% had stage I disease, 77% had estrogen-receptor positive disease and 82% had node-negative breast cancer. Only two patients had symptomatic congestive HFrEF with a one-year cumulative incidence of 3.6%; (95% confidence interval [CI], 0.09 to 13.8). Five patients had asymptomatic declines in ejection fraction with a one-year cumulative incidence of 9.1%; (95% CI, 3.9 to 20.1). The 5-year DFS was 86.4%; (95% CI, 73.6 to 93.3). Among seven relapses seen, two were due to distant metastatic breast cancer. The 5-year rate of overall survival was 90.2%; (95% CI, 78.1 to 95.8). Among five deaths, one was due to distant metastatic breast cancer. Conclusions: Among older women with stage I-III HER2-positive breast cancer who decline chemotherapy or are not chemotherapy candidates, treatment with her2 targeted therapy only without chemotherapy may offer a reasonable treatment option without an inordinate rate of cardiac toxicity. Clinical trial information: NCT00796978.