Sentinel surveillance data from 1995 to 2005 for drug users in Guangdong province, China, showed an increasing prevalence of HIV in the West region while stabilizing in the East and Center. Several factors were significantly associated with HIV infection including gender, age, sharing needles, years injecting, engaging in commercial sex, and being part of the migrant population of Guangdong. Data help effectively prioritize and target HIV prevention efforts for drug users.