Liver disease may be found in patients with primary immunodeficiency syndromes because of the high risk of infection with hepatotropic viruses related to the treatment with blood derivatives. The prevalence of liver disease in these patients and its etiology, however, is still not completely understood. We have evaluated the prevalence and the etiology of liver disease in children with different forms of primary immunodeficiencies. Thirty patients included in the study underwent molecular studies to detect common hepatotropic viruses, including hepatitis C and G viruses. Liver involvement was found in 11 of 30 (36.6%) patients. All patients with liver disease had deficiencies of specific immunity, with a prevalence in this subgroup of 47.8%. Liver disease was more severe in patients with T and B cell combined immune disorders than in those with a selective T cell immunodeficiency. Moreover, the severity of the disease correlated with an overall more rapid fatal outcome. A viral etiology was found in only six of these patients, whereas in the remaining five patients, no cause of liver injury was identified. In the virally infected patients, hepatitis C virus was the most common viral agent. In patients with immunodeficiencies, there is a high prevalence of liver disease not fully explained on the basis of the common viral infections.