We determined the effect of syringe exchange programs (SEPs) on syringe reuse patterns. Five methods were employed to estimate injections per syringe made by exchange clients in four cities. In San Francisco, Chicago, and Baltimore, self-reported data on the number of injections per syringe were obtained. In New Haven, self-reported injection frequencies were combined with syringe tracking data to derive two methods for estimating the mean injections per syringe. The average number of injections per syringe declined by at least half after establishment of SEPs in New Haven, Baltimore, and Chicago, all cities where such an analysis could be made. There were significant increases in the percentages of exchangers reporting once-only use of their syringes in San Francisco, Baltimore, and Chicago, all cities where the data were amenable to this form of analysis. Self-report and syringe tracking estimates were in agreement that SEP participation was associated with decreases in syringe reuse by drug injectors. SEP participation was associated with increases in the once-only use of syringes. These findings add to earlier studies supporting the role of SEPs in reducing the transmission of syringe-borne infections such as HIV and hepatitis.