The incidence of rabies in humans in the United States is low. However, contacts with potentially rabid animals result in thousands of human rabies postexposure prophylaxis treatments (PEPs) each year. PEP is expensive, not without risk of adverse reactions, and in many instances unnecessary. Increased reports of cases of rabies in animals (4,880 cases in 1990, 9,495 in 1993, and 7,124 in 1996) suggested that PEPs could be increasing. Application of 1981 PEP incidence rates gave an estimate of approximately 16,000 PEPs during 1996, while calculations based on annual sales of a rabies biological during 1996 gave an estimate of approximately 39,000 PEPs. Appropriate usage of PEP requires careful evaluation of human exposure scenarios and adherence to approved guidelines.