We examined use of the San Francisco needle exchange program (NEP) by 1093 injection drug users (IDUs) recruited in methadone maintenance and out-patient detoxification programs in the first 2 years after the opening of the NEP in 1988. Thirty-one percent of IDUs had ever used the NEP. IDUs who were frequent injectors, homeless, and aware of their serostatus were more likely to use the NEP. To assess self-selection of IDUs at risk for seroconversion for using needle exchange, we calculated pre-needle exchange seroconversion rates. Among 385 IDUs seen twice, the HIV seroconversion rate was 0.38% per person year among subjects who never used needle exchange, but it was 9.34% per person year among those who later used needle exchange (p = 0.003). NEP attracted a subset of IDUs at very high risk for HIV infection. Among injectors who were interviewed before and after the opening of the needle exchanges in San Francisco, the number of sharing partners did not change among IDUs who attended or among IDUs who never attended the NEP. The NEP attracted a very-high-risk subgroup of IDUs, as measured by risk behavior and pre-needle exchange HIV-seroconversion rate. NEPs should be considered prime sites for behavior-change interventions.