A population-based active-surveillance study of the Calgary Health Region (population, 929,656) was conducted from May 1999 to April 2000, to define the epidemiology of invasive Staphylococcus aureus (ISA) infections. The annual incidence was 28.4 cases/100,000 population; 46% were classified as nosocomial. Infection was most common in people at the extremes of the age spectrum and in males. Several conditions were associated with acquisition of ISA infection, and the highest risk was observed in persons undergoing hemodialysis or peritoneal dialysis and in persons infected with human immunodeficiency virus. Forty-six patients (19%) died. Significant independent risk factors for mortality included positive blood-culture result, respiratory focus, empirical antibiotic therapy, and older age. A higher systolic blood pressure at presentation was associated with reduced case-fatality rate. ISA infections are common, with several definable groups of patients at increased risk for acquisition and death from these infections. This study provides important data on the burden of ISA disease and identifies risk groups that may potentially benefit from preventive efforts.