Methicillin-resistant Staphylococcus aureus (MRSA) infections and methamphetamine use are emerging public health problems. We conducted a case-control investigation to determine risk factors for MRSA skin and soft tissue infections (SSTIs) in residents of a largely rural southeastern community in the United States. Case-patients were persons >12 years old who had culturable SSTIs; controls had no SSTIs. Of 119 SSTIs identified, 81 (68.1%) were caused by MRSA. Methamphetamine use was reported in 9.9% of case-patients and 1.8% of controls. After we adjusted for age, sex, and race, patients with MRSA SSTIs were more likely than controls to have recently used methamphetamine (odds ratio 5.10, 95% confidence interval 1.55-16.79). MRSA caused most SSTIs in this population. Transmission of MRSA may be occurring among methamphetamine users in this community.