Rabies is a viral infection that causes acute, progressive encephalitis and is considered to be universally fatal. However, during 2004, an unvaccinated Wisconsin patient received a new medical treatment and became the first documented survivor of rabies who had not received preexposure vaccination or postexposure prophylaxis (PEP), suggesting the possibility of successful future interventions. This report describes two recent patients with rabies who were treated using therapy similar to that used for the Wisconsin patient; both treatments were unsuccessful. The report also describes the concomitant epidemiologic investigations by the Indiana State Department of Health (ISDH), California Department of Health Services (CDHS), and CDC, and the local public health responses in Marshall County, Indiana, and San Joaquin and Alameda counties in California. The findings in this report underscore the continuing need for enhanced clinical awareness of possible rabies exposure to ensure prompt PEP and timely diagnosis of rabies, especially if treatment is attempted.