OBJECTIVE To evaluate the effects of methadone on QT-interval dispersion. METHODS Single-center, prospective, cohort study. METHODS Methadone maintenance treatment facility. METHODS One hundred eighteen patients who were newly admitted to the facility. Intervention. Twelve-lead electrocardiograms (ECGs) were performed in patients at both baseline and 6 months after the start of methadone therapy. RESULTS The ECGs were manually interpreted, and investigators were blinded to time interval and methadone dose. At least eight discernible ECG leads were required for study inclusion. Mean differences between baseline and follow-up rate-corrected QT (QTc) interval and QT dispersion were compared. Multivariate associations between clinical characteristics and magnitude of change in QT dispersion were assessed using linear regression. Mean +/- SD baseline QT dispersion was 32.9 +/- 12 msec, which increased to 42.4 +/- 15 msec (+9.5 +/- 18.6 msec, p<0.0001) after 6 months of therapy. The QTc increased by a similar magnitude (+14.1 msec, p<0.0001). No QT dispersion value exceeded 100 msec. The only variable associated with a greater increase in QT dispersion was antidepressant therapy (20 vs 8.5 msec, p=0.04). CONCLUSIONS Methadone modestly increased both QTc interval and QT dispersion. Increased QT dispersion reflects heterogeneous cardiac repolarization and occurs with nonantiarrhythmic agents, such as synthetic opioids. However, the magnitude of this effect appears to be substantially less with methadone than with antiarrhythmic drugs.