The objective of this study was to monitor the trend of addiction drug use and its relationship with sexually transmitted infections (STIs) among female drug users (FDUs). Serial cross-sectional surveys were conducted during 2010–2014 among FDUs in Beijing to collect information on addiction drug usage, sexual behaviors, and STI prevalence. Characteristics were analyzed and compared between traditional and synthetic drug users among FDUs by logistic regression method. A total of 3859 FDUs were surveyed during 2010–2014, with the median age being 32.7 years old. The proportion of synthetic drug users among FDUs increased from 43.7% in 2010 to 70.7% in 2014. Compared with traditional drug users, synthetic drug users were younger (P < 0.001), lacked education (P < 0.001), were unmarried (P < 0.001), and were non-local residents (P < 0.001). No significant difference was found with condom usage during sexual activity between traditional and synthetic drug FDUs. However, the engagement of commercial sexual activities (P < 0.001) and syphilis prevalence (P < 0.001) among synthetic drug users were significantly higher than traditional drug users. Synthetic drug abuse appears to be correlated with commercial sex behavior and higher syphilis prevalence among FDUs. Tailored strategies on health education to curb the prevalence of synthetic drug abuse are urgently needed in Beijing.