Background: Breast cancer is the most common cancer in women worldwide, and reproductive factors and family history of malignancy are considered as high risk factors. The present study aimed to evaluate the synergistic effect of reproductive factors and family history on breast cancer. Method: A total of 1215 breast cancer patients and 1215 control participants from two medical centers were enrolled, and reproductive factor history and family cancer history information was collected. Multivariate logistic regression analyses were performed to estimate the adjusted odds ratio (OR), and synergy index (SI) was used to assess the combined effect of potential factors. Results: Compared to the controls, a negative association between full-term pregnancy/breastfeeding and breast cancer was observed regardless of the status of family cancer history (OR: 0.675, 95% CI: 0.560-0.814 and OR: 0.631, 95% CI: 0.503-0.789 respectively) after adjustment of other confounders, while the risk effect of abortion was unproven. The synergistic effect of history of full-term pregnancy and family history of malignancy was indicated in the combined analyses with SI as 9.429 (95% CI:1.248-71.245). Conclusion: Full-term pregnancy/breastfeeding were protective factors against breast cancer and synergistic additive effect was demonstrated between no full-term pregnancy/breastfeeding and a family history of malignancy on the risk of breast cancer.