The implication of hemochromatosis (HFE) gene mutations in chronic viral hepatitis remains controversial. The aim of the present study was to measure the frequencies of the common HFE gene mutations in Moroccan subjects with chronic viral hepatitis B and C and to assess their influence on the progression of liver disease. H63D and C282Y mutations were screened by the polymerase chain reaction followed by restriction fragment length polymorphism analysis in 170 chronic hepatitis B patients, 168 chronic hepatitis C patients, and 200 healthy controls. A very small proportion of patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV; 1.8% and none, respectively) were heterozygous for the C282Y mutation, that is, rates not statistically different from those observed in healthy control (2%, P > 0.05). Similarly, the frequency of the H63D allele was not significantly different between HBV (13.8%) or HCV (14.3%) patients and controls (13.5%, P > 0.05). Multivariate analysis showed that carriers of the H63D mutation infected with HBV are at higher risk to progress towards an advanced liver disease when compared with patients infected with HBV with wild-type (OR = 2.45, 95% CI = 1.07–5.58). In contrast, no association between HFE mutated HCV-infected patients and an increased risk of disease progression was found (OR = 1.24, 95% CI = 0.61–2.50, P = 0.547). In conclusion, in Morocco the frequency of the HFE C282Y allele is very low and H63D mutation carriage occurs in almost 14% of the patients, a rate similar in chronic hepatitis patients and healthy controls. In the case of chronic hepatitis B, the carriage of the H63D variant represents a risk factor of evolution towards a more active disease. J. Med. Virol. 83:2096–2102, 2011. © 2011 Wiley Periodicals, Inc.