Immunoglobulin G subclass titers to three herpesviruses (herpes simplex; HSV; cytomegalovirus, CMV; varicella zoster virus, VZV) were examined in patients with common variable immunodeficiency (CVI) before and after immunoglobulin substitution. Like healthy controls, CVI patients expressed IgG1 and IgG3 to HSV and CMV, but only IgG1 to VZV. Individual titers varied as in healthy individuals, but as a mean, specific IgG titers were lowered in proportion to the decrease of total IgG. HSV and CMV IgG3 titers were relatively higher than the IgG1 titers in CVI patients, resulting in a lower IgG1/IgG3 ratio than in healthy individuals (P = 0.025 and 0.05, respectively). The high IgG3 titers in CVI patients could be due to subclinical reactivations of HSV and CMV in these patients. Low VZV IgG1 and absence of IgG3 could explain the increased frequency of zoster infections reported in CVI patients. After immunoglobulin substitution, herpesvirus-specific IgG1 titers increased while HSV and CMV IgG3 decreased or remained stationary. In two unsubstituted patients, HSV and CMV titers remained stationary during 1 and 5 years, respectively, while an increase of VZV IgG1 and IgG3 indicated VZV reactivation although the patients remained asymptomatic.