We assessed the types of drugs, the prevalence of HIV, syphilis, and its correlates among Shandong's drug users in China. Two consecutive cross-sectional surveys in 2009 and 2010 provided demographics, types of drugs, sexual and drug-use behaviors, and HIV-related services. Of the 1320 unique, eligible participants, 81.1% were male, two-thirds <35 years of age, 13.0% non-Shandong residents; in the past year, majority (96.4%) reported ever using methamphetamine, 3.4% using heroin, 8.6% using ≥2 types of these drugs and 8.0% injecting drugs, 63.8% having commercial sex. HIV and syphilis prevalence were 0.2% and 8.3%, respectively. In multivariable logistic regression analysis, syphilis was independently associated with female, non-Shandong residents, higher levels of education, and 2010. Synthetic drugs, especially methamphetamine, have become the predominant sources of drug addiction. The emerging epidemic of syphilis potentially driven by methamphetamine use underscored the urgency to implement an effective sex and substance use-related intervention.