Macrolide-resistant Mycoplasma pneumoniae is widespread in Asia, and severe cases of pneumonia have been described in children. Little information is available about the resistance pattern in the United States. We collected respiratory samples from 49 patients with Mycoplasma infection in the central United States between 2007 and 2010. We found a macrolide resistance rate of 8.2%. Resistance should be considered when patients with M. pneumoniae infection do not have a satisfactory response to macrolides. Alternative antibiotics include tetracyclines or fluoroquinolones.