In 2004, poisoning was second only to motor-vehicle crashes as a cause of death from unintentional injury in the United States . Nearly all poisoning deaths in the United States are attributed to drugs, and most drug poisonings result from the abuse of prescription and illegal drugs. Previous reports have indicated a substantial increase in unintentional poisoning mortality during the 1980s and 1990s. To further examine this trend, CDC analyzed the most current data from the National Vital Statistics System. This report summarizes the results of that analysis, which determined that poisoning mortality rates in the United States increased each year from 1999 to 2004, rising 62.5% during the 5-year period. The largest increases were among females (103.0%), whites (75.8%), persons living in the southern United States (113.6%), and persons aged 15-24 years (113.3%). Larger rate increases occurred in states with mostly rural populations. Rates for drug poisoning deaths increased 68.3%, and mortality rates for poisonings by other substances increased 1.3%. The largest increases were in the "other and unspecified," psychotherapeutic, and narcotic drug categories. The results suggest that more aggressive regulatory, educational, and treatment measures are necessary to address the increase in fatal drug overdoses.