Surveillance systems for acute hepatitis C allow monitoring of disease incidence trends and transmission patterns. This study aimed to describe the epidemiological profile of reported cases of symptomatic acute hepatitis C in Italy after the achievement of blood supply safety. The incidence of symptomatic acute hepatitis C since 1991 was estimated. Risk factors for acute hepatitis C were analyzed for the period 2003-2010 through a case-control study within a population-based surveillance for acute viral hepatitis. From 1991 to 2010, the incidence decreased from 2 to 0.2 per 100,000, with a more evident decrease among persons aged 15-24 years. During 2003-2010, 1,053 cases were reported. Intravenous drug use (adjusted odds ratio [(adj) OR], 30.5; 95% confidence interval [CI], 18.9-49.1), cohabitation or sexual partnership with an hepatitis C virus (HCV) carrier ((adj) OR, 11.2; 95% CI, 6.6-19.2), nosocomial exposure ((adj) OR, 6.6; 95% CI, 4.6-9.4); unsafe sexual practices ((adj) OR, 3.1; 95% CI, 1.9-5.2), and cosmetic treatments with percutaneous exposure ((adj) OR, 1.7; 95% CI, 1.2-2.4) were independently associated with acute hepatitis C. Population attributable risk estimates indicated nosocomial exposure (39.6%) and intravenous drug use (30.5%) as responsible for most cases. In conclusion, the incidence of symptomatic acute hepatitis C is declining in Italy. Currently, the most important risk factors are: having an HCV-positive household or sexual partner, unsafe sexual practices, cosmetic percutaneous treatments, intravenous drug use, and nosocomial exposure; the latter two factors are responsible for most cases. Effective prevention programs for intravenous drug users and strict adherence to universal precautions in healthcare settings are needed. J. Med. Virol. © 2012 Wiley Periodicals, Inc.