Ventricular tachycardia (VT), which causes hemodynamic instability, and ventricular fibrillation (VF) sometimes occur in patients with severe underlying cardiovascular disease such as myocardial ischemia or infarction, and are associated with high mortality. This report presents the efficacy of nifekalant hydrochloride (nifekalant), a pure class III antiarrhythmic agent, in treating life-threatening ventricular arrhythmia in such patients. From June 2000, when nifekalant became commercially available in Japan, to May 2003, 30 ischemic heart disease (IHD) patients with VT/VF resistant to direct-current (DC) countershock received nifekalant in our hospital. These 30 patients served as the nifekalant group in this study. As a control group, we also included 33 IHD patients with VT/VF that had been resistant to DC countershock upon or during hospitalization between January 1996 and May 2000 before nifekalant became commercially available. No significant differences were observed in patient background factors and treatments between the two groups. The rates of death within 48 hours of occurrence of VT/VF were significantly lower in the nifekalant group (7%, 2/30) than in the control group (27%, 9/33; P < 0.03). The rates of cardiac death during hospitalization were also significantly lower in the nifekalant group (40%, 12/30) than in the control group (67%, 22/33; P < 0.03). The rates of survival until hospital discharge were significantly higher in the nifekalant group (57%, 17/30) than in the control group (30%, 10/33; P < 0.03). Multivariate analysis of all 63 patients revealed nifekalant administration was the factor that significantly improved the mortality (odds ratio for cardiac death, 0.26; 95% confidence interval (CI), 0.07 to 0.95; P = 0.041). Nifekalant improves the prognosis for life-threatening ventricular arrhythmia in IHD patients.