Although ventricular fibrillation (VF) out-of-hospital cardiac arrest (OHCA) occurs primarily in the setting of severe ischemic heart disease (IHD), a significant proportion of events occurs in patients who do not have severe IHD. The relative effect of IHD on survival after VF OHCA is unknown. All residents of Rochester, Minnesota, who presented with a VF OHCA from November 1990 to December 2004, treated by emergency medical services, were included in the study. During the study, emergency medical services treated 208 patients (64.1 ± 13.6 years of age) for VF OHCA, with an average call-to-shock time of 6.3 ± 1.8 minutes. Of these patients, 156 had IHD and 39 had non-IHD. In 13, the underlying heart disease was unknown. Eighty-seven patients (41.8%) survived to hospital discharge with neurologic recovery (66 with IDH [42%] vs 21 with non-IHD [54%], p = 0.211)]. Five-year survival was 79 ± 6% for patients with IHD versus 100% for those with non-IHD (p = 0.047). After adjustment for other patient characteristics, IHD was not predictive of 5-year survival (hazard ratio [HR] 2.2, 95% confidence interval [CI] 0.7 to 9.8, p = 0.177). Variables associated with poor outcomes included age >65 years (HR 4.9, 95% CI 2.0 to 13.4, p = 0.0003), ejection fraction <0.35% (HR 3.0, 95% CI 1.3 to 7.3, p = 0.012), and hypertension (HR 4.9, 95% CI 1.4 to 16.3, p = 0.001). In patients with IHD, use of an implantable cardioverter-defibrillator (HR 0.32, 95% CI 0.16 to 0.88, p = 0.024) and statin therapy (HR 0.68, 95% CI 0.17 to 0.73, p = 0.001) were associated with decreased mortality. In conclusion, compared with patients with non-IHD, those with IHD had similar short- and long-term survival rates. Long-term survival in patients with IHD was primarily influenced by other co-morbid conditions. Nonetheless, in patients with IHD, use of an implantable cardioverter-defibrillator and statin therapy were associated with higher long-term survival rates.