Quantify the incremental health care costs and workplace absence and short-term disability costs, to payers and employers, of patients hospitalized for acute coronary syndrome (ACS). Retrospective study using medical insurance claims for the years 2002 to 2007. Patients were aged 18 to 64 years and hospitalized for ACS between January 1, 2003, and December 31, 2006; comparison patients without evidence of coronary artery disease were also selected. The incremental impact of ACS was estimated using weighted regression. 30,200 ACS patients were selected. Incremental annual direct costs of ACS were $40,671 (P < 0.001). For the indirect cost sub-analyses, incremental short-term disability costs of ACS were $999 (P < 0.001) and incremental absence costs were insignificant (P = 0.314) but from a small sample (N = 416). Patients with ACS impose a substantial direct cost burden on employers and payers and a substantial indirect cost burden on employers. Acute coronary syndrome is more costly to employers and payers than other health conditions that are common among employed persons. Rehospitalizations after the initial hospitalization are common and represent a large portion of the cost.