Antibody serum levels against herpes simplex type 1 virus, cytomegalovirus, viral capsid antigens of Epstein-Barr virus, and rubella virus were evaluated in a sample of the Sicilian population. Results demonstrated that HLA-DR2-positive individuals showed a significant increase in antibody titers, when compared to HLA-DR2-negative individuals. These observations seem to be in contrast with the reported association of the HLA-DR2 phenotype with an ineffective immune response against several infectious pathogens. On the other hand, an increased humoral response to viral antigens need not be interpreted as a marker for effective control of virus infections. In fact, the response to virus infections is related to the T-cell-mediated immune response restricted by class-I- or class-II-encoded proteins. Thus, the above-mentioned HLA-DR2-related susceptibility to certain viral infections could be associated with a preferential induction of an increased (although ineffective) antibody synthesis against viral antigens.