From 2000 to 2011, the rate of unintentional drug poisoning (overdose) deaths involving opioid analgesics increased 435% in Staten Island, from 2.0 to 10.7 per 100,000 residents. During 2005-2011, disparities widened between Staten Island and the other four New York City (NYC) boroughs (Bronx, Brooklyn, Manhattan, and Queens); in 2011, the rate in Staten Island was 3.0-4.5 times higher than in the other boroughs. In response, the NYC Department of Health and Mental Hygiene (DOHMH) implemented a comprehensive five-part public health strategy, with both citywide and Staten Island-targeted efforts: 1) citywide opioid prescribing guidelines, 2) a data brief for local media highlighting Staten Island mortality and prescribing data, 3) Staten Island town hall meetings convened by the NYC commissioner of health and meetings with Staten Island stakeholders, 4) a Staten Island campaign to promote prescribing guidelines, and 5) citywide airing of public service announcements with additional airing in Staten Island. Concurrently, the New York state legislature enacted the Internet System for Tracking Over-Prescribing (I-STOP), a law requiring prescribers to review the state prescription monitoring system before prescribing controlled substances. This report describes a 29% decline in the opioid analgesic-involved overdose death rate in Staten Island from 2011 to 2013, while the rate did not change in the other four NYC boroughs, and compares opioid analgesic prescribing data for Staten Island with data for the other boroughs. Targeted public health interventions might be effective in lowering opioid analgesic-involved overdose mortality rates.