Substance abuse (SA) imposes a substantial economic burden on society. This burden arises largely from indirect costs associated with lost productivity (morbidity), premature mortality, and crime. The economic impact of SA has been estimated on a national level, but state-level estimates, needed for resource allocation and policy development, are lacking. I used standard cost-of-illness methods to quantify the economic cost of SA for Washington State for 2005. The cost of SA was estimated at $5.21 billion, $832 per non-institutionalized person in the state. Translated into 2012 dollars, these costs would be $6.12 billion and $977, respectively. Categories accounting for the greatest costs were mortality ($2.03 billion), crime ($1.09 billion), morbidity ($1.03 billion), and health care ($791 million). There were 3,224 deaths (7 percent of all deaths), 89,000 years of productive life lost, and 29,000 hospital discharges in 2005 in Washington State associated with SA. Continued attention should be directed at developing effective approaches to prevent and treat SA. If successful, these efforts should reduce the future economic burden of SA.