In this study, we created a mouse model of methamphetamine cardiomyopathy that reproduces the chronic, progressive dosing commonly encountered in addicted subjects. We gradually increased the quantity of methamphetamine given to C57Bl/6 mice from 5 to 40 mg/kg over 2 or 5 months during two study periods. At the fifth month, heart weight was increased, echocardiograms showed a dilated cardiomyopathy and survival was lower in males, with less effect in females. Interestingly, these findings correspond to previous observations in human patients, suggesting greater male susceptibility to the effects of methamphetamine on the heart. Transcriptional analysis showed changes in genes dysregulated in previous methamphetamine neurological studies as well as many that likely play a role in cardiac response to this toxic stress. We expect that a deeper understanding of the molecular biology of methamphetamine exposure in the heart will provide insights into the mechanism of cardiomyopathy in addicts and potential routes to more effective treatment.