To investigate whether genetic factors linked to the human leukocyte antigens (HLA) might influence individual resistance to recurrent herpes labialis (RHL), we studied the frequencies of HLA-A, -B, and -C antigens in a sample of Sicilian population. The frequency of HLA-B35 was significantly decreased in the patient group (p corrected = 0.018). Consequently, the relative risk of development of RHL in a subject positive for HLA-B35 was 20 times smaller than in a subject who does not bear B35. Furthermore, a study was made of the possible relationship between the presence of HLA-B35 antigen and antibody titers to herpes simplex virus type 1 (HSV-1) in 62 persons affected or not by RHL. Significantly elevated titers to HSV-1 were found in the diseased group (p less than 0.001), but the geometric mean of antibody titers in HLA-B35 positive subjects was not different from that of B35 negative subjects either of RHL-affected or in healthy persons. These data are in a good agreement with the hypothesis that humoral immune responses play a marginal role in the protection from HSV-1 recurrences.