The eLEcTRA trial compared efficacy and safety of letrozole combined with trastuzumab to letrozole alone in patients with HER2 and hormone receptor (HR) positive metastatic breast cancer (MBC). Patients were randomized to either letrozole alone (arm A, n = 31) or letrozole plus trastuzumab (arm B, n = 26) as first-line treatment. Additional 35 patients with HER2 negative and HR positive tumors received letrozole alone (arm C). Median time to progression in arm A was 3.3 months compared to 14.1 months in arm B (hazard ratio 0.67; p = 0.23) and 15.2 months in arm C (hazard ratio 0.71; p = 0.03). Clinical benefit rate was 39% for arm A compared to 65% in arm B (odds ratio 2.99, 95% CI 1.01-8.84) and 77% in arm C (odds ratio 5.34, 95% CI 1.83-15.58). The eLEcTRA trial showed that the combination of letrozole and trastuzumab is a safe and effective treatment option for patients with HER2 positive and HR positive MBC.