Objective: To develop and evaluate the screening performance of a low-cost high-risk screening strategy for breast cancer in low resource areas. Methods: Based on the Multi-modality Independent Screening Trial, 6 questionnaire-based risk factors of breast cancer (age at menarche, age at menopause, age at first live birth, oral contraceptive, obesity, family history of breast cancer) were used to determine the women with high risk of breast cancer. The screening performance of clinical breast examination (CBE), breast ultrasonography (BUS), and mammography (MAM) were calculated and compared to determine the optimal screening method for these high risk women. Results: A total of 94 breast cancers were detected among 31,720 asymptomatic Chinese women aged 45-65 years. Due to significantly higher detection rates (DRs) and suitable coverage of the population, high risk women were defined as those with any of 6 risk factors. Among high risk women, the DR for BUS [3.09/1,000 (33/10,694)] was similar to that for MAM [3.18/1,000 (34/10,696)], while it was significantly higher than that for the CBE [1.73/1,000 (19/10,959), P = 0.002]. Compared with MAM, BUS showed significantly higher specificity [98.64% (10,501/10,646) vs. 98.06% (10,443/10,650), P = 0.001], but no significant differences in sensitivity [68.75% (33/48) vs. 73.91% (34/46)], positive prediction values [18.54% (33/178) vs. 14.11% (34/241)], and negative prediction values [99.86% (10,501/10,516) vs. 99.89% (10,443/10,455)]. Further analyses showed no significant difference in the percentages of early stage breast cancer [53.57% (15/28) vs. 50.00% (15/30)], lymph node involvement [22.73% (5/22) vs. 28.00% (7/25)], and tumor size ≥ 2 cm [37.04% (10/27) vs. 29.03% (9/31)] between BUS and MAM. Subgroup analyses stratified by breast densities or age at enrollment showed similar results. Conclusions: The low-cost high-risk screening strategy based on 6 questionnaire-based risk factors was an easy-to-use method to identify women with high risk of breast cancer. Moreover, BUS and MAM had comparable screening performances among high risk women.