Background: Overweight and obesity are strongly linked to poorer BC-specific outcomes, quality of life and financial burden in cancer care. Weight loss interventions have the potential to improve such outcomes. Fewer data exist on whether excess weight and post-diagnosis weight changes impact the ability of BC survivors to return to work (RTW). Methods: CANTO (NCT01993498) is a multicenter prospective longitudinal study of 12000 patients (pts) with stage I-III BC that characterizes long-term toxicities of BC treatment. Of 5801 pts enrolled from 2012-2014 (last data lock), we identified 1874 pts who were professionally active at BC diagnosis, ≥5 years (yrs) younger than minimum legal retirement age (62 yrs) and with updated work status 2 yrs after diagnosis. Logistic regression models evaluated the impact of body mass index (BMI) at diagnosis and of weight changes over 2 yrs after diagnosis on odds of non-RTW, adjusting for age, education, income, BC treatment and recreational physical activity (PA). Results: 37% pts were overweight or obese at diagnosis (BMI ≥25 kg/m²): 34% of them gained ≥5% and 16% lost ≥5% weight after diagnosis. Rates of non-RTW at 2 yrs were significantly higher in overweight or obese vs under or normal weight pts (27% vs 18%, p≤.001; adjusted odds ratio 1.37, 95% Confidence Interval [CI] 1.04-1.80, p = .017). Overweight and obese pts who did not RTW experienced higher increments in weight (mean [95% CI]: +3.6% [+2.3, +4.9] vs +1.5% [+0.8, +2.2]) and reported more modest changes in PA (mean [95% CI]: +1.0 [-1.4, +3.5] vs +2.1 [+0.8, +3.3] MET-h/week) vs those who did RTW. Weight changes independently impacted odds of non-RTW in overweight and obese pts (p for interaction weight change*BMI ≤.001): a 5% weight gain was associated with 17% increase in adjusted odds of non-RTW (95% CI 2-35%, p = .024), whereas a loss ≥5% with 60% reduced odds of non-RTW vs weight gain (95% CI 18-82%, p = .013). Conclusions: Excess weight and weight changes are significantly associated with occupational reintegration after BC in overweight and obese pts. Randomized studies testing dedicated weight control interventions should also measure outcomes of social rehabilitation in this large subset of survivors. Clinical trial information: NCT01993498