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Objectives: To analyze the data (epidemiology, mode of transmission, course, and outcome) of a large series of patients with acute hepatitis C (AHC) in France., Methods: Prospective multicenter register, observational study., Results: A cohort of 126 patients with AHC was prospectively enrolled between 1999 and 2007. Fifteen (12%) were HIV coinfected. Suspected modes of hepatitis C virus transmission were drug use (38%), sexual contact (21%), nosocomial transmission (18%), and occupational exposure (12%). For 40% of the patients, AHC was revealed by jaundice. Spontaneous viral clearance occurred in 40% of the 72 patients observed for 3 months without treatment. Only jaundice and nosocomial/occupational transmission were predictive of spontaneous viral clearance. Ninety patients were treated with standard or pegylated interferon-alpha alone (58%) or in combination with ribavirin (42%), for 24 weeks or less in 90%. In intention-to-treat, a sustained viral response was obtained in 58 of 78 (74%) hepatitis C virus monoinfected patients [19 of 22 (86%) with 24 weeks of pegylated interferon-alpha alone], but only six of 12 (50%) of HIV coinfected patients., Conclusion: AHC remains rare, and drug and sexual transmission are predominant. A 3-month follow-up after diagnosis avoids treatment for four out of 10 patients. Antiviral treatment is highly effective, 24 weeks of pegylated interferon-alpha alone being a good option.