Primary cultures were established with epidermal cells from the skin of 11 patients with frequent episodes of herpes simplex labialis and 13 control subjects with titers of neutralizing antibody to herpes simplex virus (HSV) type 1 but no history of herpetic disease. Confluent monolayers were exposed to HSV type 1 strain E1l5, and the infection was monitored by assay of the rate of virus appearance in the culture medium. The mean slope of the virus growth curves ([log₁₀ pfu/ml/log₁₀ hr) was 9.0 in cultures from patients vs. 9.5 in cultures from controls, and the respective mean titers of virus 53 hr after infection were 10^6.8 and 10^6.5 (differences not statistically significant). Genetically controlled host factors may play some role in the clinical,response to HSV infection, but variation in the susceptibility of epidermal cells, the natural target for HSV, is not one of the critical determinants.