Injection drug users (IDUs) are at increased risk for many health problems, including acquisition of human immunodeficiency virus (HIV) and hepatitis B and C. These risks are compounded by barriers in obtaining legal, sterile syringes and in accessing necessary medical care. In 1999, we established the first-ever syringe prescription program in Providence, Rhode Island, to provide legal access to sterile syringes, reduce HIV risk behaviors, and encourage entry into medical care. Physicians provided free medical care, counseling, disease testing, vaccination, community referrals, and prescriptions for sterile syringes for patients who were not ready to stop injecting. We recruited 327 actively injecting people. Enrolled participants had limited stable contact with the health care system at baseline; 45% were homeless, 59% were uninsured, and 63% did not have a primary care physician. Many reported high-risk injection behaviors such as sharing syringes (43% in the last 30 days), reusing syringes (median of eight times), and obtaining syringes from unreliable sources (80%). This program demonstrates the feasibility, acceptability, and unique features of syringe prescription for IDUs. The fact that drug use is acknowledged allows an open and frank discussion of risk behaviors and other issues often not disclosed to physicians. The syringe prescription program in Providence represents a promising and innovative approach to disease prevention and treatment for IDUs.