The occurrence of silent myocardial ischemia (SMI) and serious arrhythmias during hemodialysis (HD) has been well documented. However, it is unclear whether these changes are due to epicardial coronary artery disease (CAD). We conducted a prospective study to assess whether SMI and arrhythmias during HD correlated with angiographically demonstrable CAD. Twenty-three patients with end-stage renal disease on maintenance HD underwent 48-hour Holter monitoring, beginning 24 hours prior to a HD session. All patients underwent biochemical evaluation, coronary angiography, and echocardiography. Holter monitoring showed SMI during HD in 22% cases. A significant increase in the frequency of ventricular ectopics (VEs) was noted during and after HD. Patients who showed SMI during HD and VEs prior to initiation of dialysis were more likely to develop significant ventricular arrhythmias during and after HD. Epicardial CAD was documented in four patients, and it did not correlate with SMI. To conclude, HD is an arrhythmogenic process. SMI during dialysis is probably not due to epicardial CAD but predisposes to clinically significant ventricular arrhythmias during and after HD. The cause of SMI during HD in patients without demonstrable CAD needs further investigation.