OBJECTIVES Alprazolam is a frequently prescribed benzodiazepine associated with abuse and misuse that can lead to fatalities. This study's aims were to: 1) describe the characteristics of alprazolam-related death cases; 2) describe the comorbidities, co-ingested drugs, and mean alprazolam concentrations of decedents; and 3) compare characteristics between alprazolam and non alprazolam-related death cases. METHODS Data from all drug-related deaths in West Virginia from January 1, 2005 to November 16, 2007 were extracted from the Forensic Drug Database. Chi square tests compared categorical descriptive statistics between alprazolam and non-alprazolam cases. One-way ANOVA compared mean alprazolam blood concentrations based upon numbers of other ingested drugs. RESULTS Of the 1199 drug-related deaths in the database, alprazolam was a contributing cause in 204 (17.0%) cases. It was involved in an increasing number of drug-related deaths over time. The mean age of alprazolam cases was 39.6 (+11.2) years; most were male (66.3%) and white (96.0%), with the deaths ruled accidental (90.2%). There was a prescription for alprazolam in over half the cases (52.5%); approximately one-third (33.8%) had a history of substance abuse or cardiovascular disease. At least one other drug was a contributor to death in 97.5% of the alprazolam cases, with an opiate detected in most cases (88.7%). The mean alprazolam blood concentration was significantly higher when taken alone than when ingested with one or more drugs (p<0.001). More alprazolam decedents were obese (43.9%) compared to non-alprazolam decedents (32.9%) (p=0.005). Alprazolam cases had a significantly greater average number of drugs implicated in death (2.9+1.0) than non-alprazolam cases (2.3+1.3) (p<0.001). CONCLUSIONS Alprazolam-associated deaths are a significant public health problem in West Virginia; these cases have characteristics that can differ from other drug death cases. Certain drug combinations involving alprazolam may pose a greater risk for serious adverse events.