Background: Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial. Methods: In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial's stratification factors. All statistical tests were two-sided. Results: Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03, P =.10) and statistically significantly improved OS (multivariable: HR=0.63, 95% CI=0.48 to 0.82, P <.001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n=2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n=692) had superior DFS (multivariable: HR=0.72, 95% CI=0.55 to 0.92, P =.01) and OS (multivariable: HR=0.59, 95% CI=0.39 to 0.90, P =.01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab. Conclusions: Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib-based therapy.