Background: Obesity is associated with worse outcomes in hormone receptor-positive (HR+) EBC. However, the association between obesity and prognosis in HER2+ EBC remains unclear. We aimed to determine the impact of BMI at diagnosis and weight change after treatment on the outcomes of HER2+ EBC pts. Methods: ALTTO was a phase 3 trial of HER2+ EBC pts. BMI was collected at baseline and at the 2-year visit. WHO BMI categories were used: underweight < 18.5 kg/m², normal weight 18.5-24.9 kg/m², overweight 25-29.9 kg/m², and obese ≥30 kg/m². A change in weight from baseline of ≥5.0% and ≤5.0% was categorised as weight gain and weight loss, respectively. The impact of baseline BMI and weight change at the 2-year visit on disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS) were investigated. Multivariate analyses adjusting for baseline pts and tumor characteristics were performed. The impact of weight change was assessed using a landmark analysis. Results: A total of 8,381 pts were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), 1,707 (20.4%) were underweight, normal weight, overweight and obese at baseline, respectively. Compared to normal weight pts, being obese at diagnosis was associated with a significant worse DDFS (adjusted hazard ratio [aHR] 1.25; 95% CI 1.04-1.50) and OS (aHR 1.27; 95% CI 1.01-1.60), and a trend towards worse DFS (aHR 1.14; 95% confidence interval [CI] 0.97-1.32). Weight loss ≥5.0% at the 2-year visit was associated with poorer outcomes: DFS (aHR 1.34; 95% CI 1.05-1.71), DDFS (aHR 1.46; 95% CI 1.07-1.98) and OS (aHR 1.83; 95% CI 1.18-2.84). A similar trend, although not significant, was observed for weight gain ≥5.0%. Results were affected by hormone receptor status and menopausal status but not by anti-HER2 treatment. Grade 3-4 toxicities, pts with ≥1 serious adverse event and treatment discontinuation were more frequent in obese patients. Conclusions: In HER2+ EBC pts, obesity at baseline is a poor prognostic factor. Weight changes during treatment and follow-up impacts clinical outcomes: this calls for the need of dietary counselling and physical exercise in the context of survivorship programs. Clinical trial information: NCT00490139