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Background: The USA300 strain of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause severe infection and is increasingly recognized as a cause of community outbreaks. In 2004, an outbreak was identified in the Calgary Health Region (CHR)., Methods: MRSA isolates were identified with standard methods at a central regional laboratory and typed via pulsed-field gel electrophoresis (PFGE). Isolates were tested by PCR for mecA, Panton-Valentine leukocidin (PVL), SCCmec, and spa genes. Cases were defined as such if a clinical isolate of the USA300 strain was noted between January 1 and September 30, 2004, and the patient had lived or traveled in CHR within 2 years before symptom onset. Demographic, clinical and risk data on all such cases were collected from several sources for statistical analysis. A case was defined as high-risk if the patient had a history of drug use, homelessness or incarceration., Results: Of 40 isolates with the USA300 PFGE pattern, all tested positive for PVL, SCCmec type IVa and spa type 008. Almost all infections (39/40, 98%) involved skin and soft tissues, except for 1 death from necrotizing hemorrhagic pneumonia; a notable proportion (38%) required hospital admission or intravenous antimicrobial therapy. The outbreak centred on the high-risk population in CHR (70%; risk ratio 169.4, 95% confidence interval 86.1-333.0)., Interpretation: People with histories of illicit drug use, homelessness or recent incarceration were at highest risk for infection with CA-MRSA. The emergence and spread of this virulent strain has important implications for treatment and public health in Canada.