We assessed fatal drug overdose and poisoning case surveillance by a regional poison control center, comparing it with medical examiner determinations of death by poisoning over the same 2-year period and from the same catchment area. We studied 358 fatal cases of poisoning or drug overdose reported by a medical examiner and 10 fatal cases of poisoning or drug overdose reported by a poison control center, analyzing demographics and other case-associated factors with with possible successful poison control center case surveillance. Of the medical examiner cases, 245 (68%) were prehospital deaths. Of the remaining 113 emergency department or hospital cases, only 5 (4.4%) were also reported to the poison control center. Compared with cases involving illicit drugs, other narcotics, and sedative drugs, those that involved other prescription drugs (relative odds, 30.6; 95% confidence interval, 2.7 to 351) and over-the-counter products and other substances (odds ratio, 18.9; 95% confidence interval, 1.4 to 257) were significantly more likely to be reported to the poison control center. Most fatal cases of poisoning and drug overdose are not detected through poison control center surveillance. For prevention and treatment, health planners and policy makers should recognize the implications of case underreporting.