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Data System. The American Association of Poison Control Centers (AAPCC) and the Centers for Disease Control and Prevention (CDC) jointly monitor the National Poison Data System (NPDS) for incidents of public health significance (IPHSs). Data Collection/Processing. NPDS is the data repository for US poison centers, which together cover all 50 states, the District of Columbia, and multiple territories. Information from calls to poison centers is uploaded to NPDS in near real time and continuously monitored for specific exposures and anomalies relative to historic data. Data Analysis/Dissemination. AAPCC and CDC toxicologists analyze NPDS-generated anomalies for evidence of public health significance. Presumptive results are confirmed with the receiving poison center to correctly identify IPHSs. Once verified, CDC notifies the state public health department. Implications. During 2013 to 2018, 3.7% of all NPDS-generated anomalies represented IPHSs. NPDS surveillance findings may be the first alert to state epidemiologists of IPHSs. Data are used locally and nationally to enhance situational awareness during a suspected or known public health threat. NPDS improves CDC's national surveillance capacity by identifying early markers of IPHSs.