Hepatitis C virus (HCV) is spontaneously cleared in 15% to 45% of individuals during primary infection. To define the role of alcohol, race, and HBV or HIV coinfections in natural HCV clearance, we examined these parameters in 203 spontaneously HCV-recovered subjects (HCV Ab+/RNA- subjects without prior antiviral therapy) and 293 chronically HCV-infected patients (HCV Ab+/RNA+). Subjects were identified from 1,454 HCV antibody-seropositive US veterans tested for HCV RNA between January 2000 and July 2002 at the Philadelphia Veterans Affairs Medical Center. In univariate analysis, alcohol use disorder (odds ratio [OR] 0.52; 95% CI, 0.31-0.85; P = .006) and black race (OR 0.65; 95% CI, 0.44-0.96; P = .024) were both associated with decreased likelihood of spontaneous HCV clearance. In multivariate analyses adjusting for race, HIV infection, age, and alcohol use disorder, alcohol remained strongly associated with reduced HCV clearance (OR 0.49; 95% CI, 0.30-0.81; P = 0.005). In contrast, the association between black race and viral clearance was no longer statistically significant (adjusted OR 0.72; 95% CI, 0.48-1.09; P = .125). HIV coinfection was negatively associated with HCV clearance (OR 0.37; 95% CI, 0.16-0.83; P = .016), while HBV coinfection was positively associated with HCV clearance (unadjusted OR 5.0; 95% CI, 1.26-28.6; P = .008). In conclusion, the likelihood of spontaneous clearance of HCV may be influenced by alcohol and viral coinfections. (Hepatology 2004;40:892-899).