To demonstrate that injecting drug use is a major risk factor of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection and injecting drug users may be a reservoir of CA-MRSA infection in our community, we conducted a matched case-control study. Cases were CA-MRSA-infected patients at University of California, Davis, Medical Center, Sacramento, CA, from December 1, 2003, to May 31, 2004. Two control groups were community-associated methicillin-susceptible S. aureus (CA-MSSA)-infected patients and a randomly selected uninfected patient group in the same hospital. Controls were matched to cases by age and isolate culture date. One hundred twenty-seven CA-MSSA patients and 381 randomly selected uninfected controls were selected to match the 127 CA-MRSA cases. The adjusted odds ratio of injecting drug use compared with the CA-MSSA group was 2.11 (95% confidence interval [CI], 1.1-4.3) and 4.09 (95% CI, 2.2-7.5) compared with the uninfected group. We suggest that injecting drug use is a significant risk factor for CA-MRSA infection, which could contribute to the increasing prevalence of CA-MRSA in an urban community.