BACKGROUND Cardiac disease is an important cause of morbidity and mortality in Irish Wolfhounds (IWs), but its prevalence and clinical characteristics in North American IWs are incompletely described. OBJECTIVE That atrial fibrillation (AF) is a diagnostic marker of echocardiographic abnormalities, and that clinical characteristics predict development of IW cardiomyopathy (IWCM). To define the prevalence of arrhythmias and echocardiographic abnormalities in North American IWs. METHODS Six hundred and forty-five adult IWs presented for screening examinations intended to identify familial cardiac disease. METHODS In this retrospective cohort study, reference intervals defined based on echocardiographic data from IW classified as normal, were used to define the prevalence of structural and functional abnormalities. A logistic model was developed to identify clinical findings that predict future development of IWCM. RESULTS The prevalence of AF was 8.9% (95% confidence interval [CI], 6.6-11.2) of which 55.5% had echocardiographic abnormalities. IWCM defined by left atrial enlargement, left ventricular dilatation, and systolic dysfunction had a prevalence of 1.8% (0.72-2.8). Positive and negative likelihood ratios for AF in the identification of IWCM were, respectively, 10.8 (7.29-16) and 0.2 (0.06-0.69). Multivariable logistic regression identified AF (odds ratio [OR]; 10.6, 95% CI, 2.67-42.3) and male sex (OR; 3.8, 95% CI, 1.02-14) as predictors of future development of IWCM. CONCLUSIONS Atrial fibrillation is common in North American IW. It occurs in association with structural cardiac disease but also in its absence. Irish Wolfhounds cardiomyopathy is characterized by chamber enlargement but minimally decreased ejection phase indices of myocardial function. Atrial fibrillation is a risk factor for future development of IWCM.