It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In this study, we examined the incidence of cardiac arrhythmias in cardiac asymptomatic HH subjects (NYHA functional class I), and compared it to that in age/gender-matched normal volunteers. The 42 HH subjects and 19 normal volunteer control subjects recruited through the NHLBI-sponsored "Heart Study of Hemochromatosis" completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The HH subjects were classified as newly diagnosed (Group A) and chronically treated subjects (Group B). All HH subjects had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations which are known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be higher in the combined HH groups than the controls. Supraventricular ectopy was more frequently noted in Group B as compared to the controls (ectopy rate per hour; 11.1±29.9 vs. 1.5±3.5, P < 0.05 by Kurskal Wallis test). No examples of heart block, other than first degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in Group A subjects. No life threatening arrhythmias were observed in our HH subjects. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic HH subjects. A larger clinical study is warranted to further clarify our observation.