Rat-bite fever (RBF) is a rare, systemic illness caused by infection with Streptobacillus moniliformis. RBF has a case-fatality rate of 7%-10% among untreated patients. S. moniliformis is commonly found in the nasal and oropharyngeal flora of rats. Human infection can result from a bite or scratch from an infected or colonized rat, handling of an infected rat, or ingestion of food or water contaminated with infected rat excreta. An abrupt onset of fever, myalgias, arthralgias, vomiting, and headache typically occurs within 2-10 days of exposure and is usually followed by a maculopapular rash on the extremities. This report summarizes the clinical course and exposure history of two rapidly fatal cases of RBF identified by the CDC Unexplained Deaths and Critical Illnesses (UNEX) Project in 2003. These cases underscore the importance of 1) including RBF in the differential diagnoses of acutely ill patients with reported rat exposures and 2) preventing zoonotic infections among persons with occupational or recreational exposure to rats.