Objective: To explore the value of contrast-enhanced ultrasound in the biopsy of patients with breast imaging reporting and data system (BI-RADS) score of 4 lesions. Methods: Total of 136 cases of breast BI-RADS scores of 4 lesions admitted to Dongguan People′s Hospital from June 2017 to May 2018 were enrolled and randomly divided into contrast-enhanced ultrasound group and general ultrasound group, 68 cases in both group. The contrast-enhanced ultrasound group received contrast-enhanced ultrasound-guided breast nodule biopsy, and the general ultrasound group received general ultrasound-guided breast nodule biopsy. The success rate of puncture, the number of puncture needles, the satisfaction rate of the materials, the diagnostic sensitivity, the diagnostic specificity, the diagnostic coincidence rate, and the incidence of adverse puncture reactions were compared between two groups. Results: The puncture success rate of both groups were 100%. The number of puncture needles in contrast-enhanced ultrasound group was (2.89±0.56)times, and the general ultrasound group was (2.93±0.62)times, with no statistically significant difference (P>0.05). The satisfaction rate of materials in the contrast-enhanced ultrasound group was 100%(68/68), and the general ultrasound group was 94.12%(64/68), with no statistically significant difference (P>0.05). The sensitivity in the contrast-enhanced ultrasound group and the general ultrasound group were 88.89%(32/36) and 81.82%(27/33), respectively, with no statistically significant difference (P>0.05). The specificity and coincidence rate in contrast-enhanced ultrasound group were 100%(32/32) and 94.12%(64/68), which were higher than 80.65%(25/31) and 81.25%(52/64) of the general ultrasound group, with statistically significant difference (P<0.05). The incidence of adverse reactions in the general ultrasound group and the contrast-enhanced ultrasound group were 10.94%(7/64) and 2.94%(2/68), respectively, with no statistically significant difference (P>0.05). Conclusions The contrast-enhanced ultrasound-guided breast nodule biopsy can achieve high puncture success rate in patients with breast cancer with BI-RADS scores 4 lesions, and help to confirm lesion activity, necrotic liquefaction area, more accurate localization, improved material satisfaction rate and biopsy, diagnostic efficacy, with significant clinical value.