Breast tissue is particularly susceptible to exposures between menarche and first pregnancy, and a longer interval between these reproductive events is associated with elevated breast cancer risk. Physical activity during this time period may offset breast cancer risk, particularly for those at highest risk with longer menarche-to-first-pregnancy intervals. We used data from 65,576 parous women in the Nurses’ Health Study II free of cancer in 1989 (baseline) and recalled their leisure-time physical activity at ages 12-34 in 1997. Current activity was collected at baseline and over follow-up. Relative risks (RRs) were estimated using multivariable Cox proportional hazards regression models. Between 1989 and 2011, 2,069 invasive breast cancer cases were identified. Total recreational activity between menarche and first pregnancy was not significantly associated with the risk of breast cancer. However, physical activity between menarche and first pregnancy was associated with significantly lower breast cancer risk among women in the highest category of a menarche-to first-pregnancy interval (?20 years; RR for the highest versus the lowest quartile?=?0.73, 95% confidence interval?=?0.55-0.97; Ptrend ?=?0.045; Pinteraction ?=?0.048). This was not observed in women with a shorter interval. Physical activity between menarche and first pregnancy was associated with a lower risk of breast cancer among women with at least 20 years between these reproductive events. This may provide a modifiable factor that women can intervene on to mitigate their breast cancer risk associated with a longer interval.