Objective To understand the effect of comprehensive prevention and control strategy on the prevention and control of surgical site infection (SSI) in breast surgery. Methods From December 2007 to June 2008 and July 2008 to November 2019, prospective and targeted monitoring methods were adopted respectively to investigate and analyze the causes for the increased incidence of 4 cases of SSI during two periods. According to the survey results, targeted prevention and control measures were taken, including control of the impact of new adjuvant chemotherapy, attention to drainage tube maintenance, improvement of operation manipulation to shorten drainage time, special attention of senior physicians and improvement of drainage methods. Results From December 2007 to December 2019, 4 951 cases of breast surgery were monitored, there were 81 cases of SSI, infection rate was 1.64%. Targeted prevention and control measures were taken according to infection characteristics in each period, incidence of SSI decreased significantly (all P<0.01). Incidence of SSI showed a linear decreasing trend (9.09%, 5.39%, 3.59%, 1.90%) in each period of increased infection rate, difference was statistically significant (χ²=8.16, P=0.004). Conclusion According to the characteristics of infection in different periods, in-depth exploration on prevention and control measures as well as finding out key points can effectively prevent and control the occurrence of healthcare-associated infection.