Combination treatment of ledipasvir and sofosbuvir (LDV/SOF) is first-line treatment for patients with chronic hepatitis C genotype 1 in the United States, Europe, and Japan. However, the influence of LDV/SOF on the cardiovascular system is poorly characterized. A total of 470 chronic hepatitis C patients who started LDV/SOF treatment between September 2015 and February 2016 at nine hospitals in Japan were prospectively enrolled in this study. Corrected QT (QTc) prolongation was defined as a QTc interval ≥450 milliseconds. The sustained virologic response rate was 96.0% (451/470), and the discontinuance rate due to adverse effects was 0.9% (4/470). Among 395 patients whose electrocardiogram was evaluated over time and compared with baseline, the QTc interval was significantly prolonged during treatment and returned to baseline levels 12 weeks after the end of treatment. Twenty-four of 376 patients with baseline QTc intervals <450 milliseconds experienced on-treatment QTc prolongation. Higher aspartate aminotransferase-to-platelet ratio index scores (≥0.76; odds ratio, 4.375; P = 0.005) and longer QTc intervals (≥416 milliseconds; odds ratio, 4.823; P = 0.003) at baseline were significantly associated with on-treatment QTc prolongation on multivariate analysis. Patients with cirrhosis showed significantly longer QTc intervals than those without cirrhosis during treatment but not at baseline, and they developed on-treatment QTc prolongation at a higher rate than patients without cirrhosis. No cardiovascular events occurred, except for 1 patient who developed paroxysmal supraventricular tachycardia. Conclusion: Newly developed QTc prolongation was observed in 6.4% of Japanese patients during treatment and was associated with more advanced fibrosis. (Hepatology Communications 2018; 00:000-000).